Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient

ABSTRACT

A peroxisome proliferator activated receptor regulator containing a carboxylic acid derivative of formula (I)  
                 
 
     (wherein all symbols are as defined in the specification), a non-toxic acid thereof or a hydrate thereof as active ingredient.  
     Because of having an effect of regulating PPAR, a compound of formula (I) is useful as a hypoglycemic agent, a hypolipidemic agent, a preventive and/or a remedy for diseases associating metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipemia, atherosclerosis, hypertension, circulatory diseases, overeating, coronary heart diseases, etc., an HDL cholesterol-elevating agent, an LDL cholesterol and/or VLDL cholesterol-lowering agent and a drug for relief from, risk factors of diabetes or syndrome X.

TECHNICAL FIELD

[0001] The present invention relates to a carboxylic acid derivative anda peroxisome proliferator activated receptor regulator containingcarboxylic acid derivative as active ingredient.

[0002] More particularly, the present invention relates to a compound ofthe formula (I)

[0003] (wherein, all the symbols are the same meanings as definedhereafter), non-toxic salt thereof and hydrate thereof, process forproducing the same and peroxisome proliferator activated regulatorcontaining the same as an active ingredient.

BACKGROUND

[0004] Recently in the study of transcription factors concerned withmarker genes expression in adipocytes differentiation, peroxisomeproliferator activated receptor (abbreviated as PPAR hereinafter), whichis one of intranucler receptors, has been focused. cDNAs of PPAR werecloned from various kinds of animals, and plural isoform genes werefound, particularly in mammals three types of isoforms (α, δ, γ) areknown (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); GeneExpression,. 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431(1996); Mol. Endocrinology., 6, 1634 (1992)). PPARγ isoform ispredominantly expressed in adipose tissues, immune cells, adrenal gland,spleen, small intestine. PPAR α isoform is mainly expressed in adiposetissue, liver, retina, and PPAR δ isoform is widely expressed withoutspecificity for tissue (see Endocrinology., 137, 354 (1996)).

[0005] On the other hand, the following thiazolidine derivatives areknown as agents for the treatment of non-insulin dependent diabetesmellitus (NIDDM) and are hypoglycemic agents which are used for theimprovement of hyperglycemia in the patients suffering from diabetes.They are also effective for the improvement of hyperinsulinemia, glucosetolerance and decrease of serum lipid and therefore they are thought tobe considerably hopeful as agents for the treatment of insulinresistance.

[0006] One of the target proteins in the cells of these thiazolidinederivatives is exactly PPARγ and it is resolved that they enhance thetranscription activity of PPARγ (see Endocrinology., 137, 4189 (1996);Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953(1995)). Therefore, a PPARγ activator (agonist) which enhances itstranscription activity is thought to be hopeful as a hypoglycemic agentand/or a hypolipidemic agent. Furthermore, since a PPARγ agonist isknown to promote the expression of PPARγ protein itself (Genes &Development., 10, 974 (1996)), an agent which increases the expressionof PPARγ protein itself as well as PPARγ activating agent is alsothought to be clinically useful.

[0007] Among all of nuclear receptors, PPARγ is related to adipocytesdifferentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 8, 803(1995)). It is known that thiazolidine derivatives which activate thisreceptor promote adipocytes differentiation. Recently it was reportedthat thiazolidine derivatives increase fat mass and cause man to gainweight and to become obese (see Lancet., 349, 952 (1997)). Therefore, itis also thought that antagonists which inhibit PPARγ activity and agentsthat decrease the expression of PPARγ protein itself are also clinicallyapplicable. On the other hand, a compound that phosphorylates PPARγprotein and decreases its activity is reported (Science., 274, 2100(1996)). This implies that an agent which does not bind on PPARγ proteinas a ligand, but inhibits its activity is also clinically applicable.

[0008] From these, PPARγ activators (agonists) and PPARγ regulators forits expression that can increase the expression of the protein itselfare expected to be useful as hypoglycemic agents, hypolipidemic agents,and agents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity, syndrome X,hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia,atherosclerosis, hypertension, circulatory diseases and overeating etc.

[0009] On the other hand, antagonists that inhibit the transcriptionactivity of PPARγ or PPARγ regulators that inhibit the expression of theprotein itself are expected to be useful as hypoglycemic agents andagents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity and syndrome X etc.,hyperlipidemia, atherosclerosis, hypertension and overeating etc.

[0010] The following fibrate compound (e.g. chlofibrate) is known as ahypolipidemic agent.

[0011] And, it is also resolved that one of the target proteins in thecells of fibrate compounds is PPARα (See Nature., 347, 645 (1990); J.Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598(1993)). From these facts, PPARα regulators which can be activated byfibrate compounds are thought to have a hypolipidemic effect, and sothey are expected to be useful as agents for prevention and/or treatmentof hyperlipidemia etc.

[0012] Besides, it has been recently reported that PPAR α possessesanti-obese activity in the specification of WO 9736579. In addition, itwas reported that the elevation of high density lipoprotein (HDL)cholesterol level and the reduction of low density lipoprotein (LDL)cholesterol, very low density lipoprotein (VLDL) cholesterol andtriglyceride levels were induced by activation of PPAR α (J. Lipid Res.,39, 17 (1998)). It was also reported that composition of fatty acids inblood, hypertension and insulin resistance were improved byadministration of bezafibrate which is one of fibtrate compounds(Diabetes., 46, 348 (1997)).

[0013] Therefore, agonists that activate PPARα and PPARα regulators thatpromote expression of PPARα protein itself are useful as hypolipidemicagents and agents for treatment of hyperlipidemia, and are expected tohave HDL cholesterol level-elevating effect, LDL cholesterol and/or VLDLcholesterol levels-lowering effect, inhibition on the progress ofatherosclerosis and anti-obese effect. Therefore, they are thought to behopeful agents for the treatment and/or prevention of diabetes ashypoglycemic agents, for the improvement of hypertension, for the relieffrom risk factor of syndrome X and for the prevention of occurrence ofischemic coronary diseases.

[0014] On the other hand, few reports are found on ligands that activatePPARδ significantly or on biological activities associated with PPAR δ.

[0015] PPARδ is sometimes called PPARβ, or it is also called NUC1 inhuman. Until now, as for activity of PPARδ, it is disclosed in thespecification of WO 9601430 that hNUC1B (PPAR subtype whose structure isdifferent from that of human NUC1 in one amino acid) inhibited thetranscription activities of human PPARα and thyroid hormone receptor.Recently in the specification of WO 9728149, it was reported that thecompounds, which possessed high affinity to PPARδ protein and whichcould activate PPARδ significantly (i.e. agonists) were found out andthat they had HDL (high density lipoprotein) cholesterol level-elevatingactivity. Therefore, agonists that can activate PPARδ are expected tohave HDL cholesterol level-elevating effect, and so they are expected tobe useful for the inhibition on the progress of atherosclerosis andtreatment thereof, as hypolipidemic agents and hypoglycemic agents, forthe treatment of hyperlipidemia, as hypoglycemic agents, for thetreatment of diabetes, for the relief from risk factor of syndrome X,and for the prevention of occurrence of ischemic coronary diseases.

[0016] As for PPAR regulators, the following compounds were reportedbesides the above-mentioned thiazolidine derivatives and fibratecompounds.

[0017] For example, in WO9731907, it is disclosed that the compounds ofthe formula (A)

[0018] (wherein, A^(A) is phenyl, in which the said phenyl may besubstituted with one or more substituent(s) selected from groupconsisting of halogen, C1-6 alkyl, C1-3 alkoxy, C1-3 fluoroalkoxy,nitrile or —NR^(7A)R^(8A) (R^(7A) and R^(8A) each independently, ishydrogen or C1-3 alkyl);

[0019] B^(A) is (5- or 6-membered heterocyclic ring containing at leastone hetero atom selected from O, N and S)—C1-6 alkylene-, in which thesaid heterocyclic ring may be substituted with C1-3 alkyl;

[0020] Alk^(A) is C1-3 alkylene;

[0021] R^(1A) is hydrogen or C1-3 alkyl;

[0022] Z^(A) is —(C1-3 alkylene)phenyl or —NR^(3A)R^(4A))

[0023] or pharmaceutically acceptable salts thereof possess PPARγagonist activity (the necessary parts in explanation of symbols areshown).

[0024] On the other hand, in JP-A-9-323982, it is disclosed that thepropionic acid derivatives of the formula (B)

[0025] (wherein, R^(′B) is substituted or unsubstituted aromatichydrocarbon, substituted or unsubstituted aliphatic hydrocarbon ring,substituted or unsubstituted heterocyclic ring or substituted orunsubstituted condensed heterocyclic ring, R^(5B) is lower alkyl),R^(4B) s hydrogen or lower alkyl, R^(6B) is hydrogen or R^(6B) andR^(9B) taken together form double bond, R^(7′B) is hydrogen, hydroxy,carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted lower alkyl, substituted or unsubstituted carbamoyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted aralkyloxycarbonyl or —Y^(B)—R^(8B) (in which Y^(B) is—NH— or O, R^(8B) is substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl),R^(9B) is hydrogen, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxycarbonyl, R^(10B) is hydroxy,substituted or unsubstituted amino, substituted or unsubstituted loweralkoxy, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryloxy or substituted or unsubstituted aralkyloxy)

[0026] or pharmaceutically acceptable salts thereof possess hypoglycemicaction and hypolipidemic action. In addition, JP-A-8-325264,JP-A-8-325250, WO9638415 and WO9800137 have also disclosed thatanalogous compounds possess hypoglycemic action and hypolipidemicaction.

DISCLOSURE OF THE INVENTION

[0027] As the result of energetic investigations in order to findcompounds possessing regulating action on PPAR, the present inventorshave found that the purpose has been accomplished by the compound of theformula (I) and have completed the present invention.

[0028] The present invention relates to,

[0029] (1) a compound of the formula (I)

[0030] (wherein,

[0031] A¹ is C1-4 alkylene,

[0032] A² is C2-8 alkylene, C3-8 alkenylene or C3-8 alkynylene (with theproviso that (a) when E² is —O— or —S(O)_(m)—, A² represent neither C3alkenylene nor C3 alkynylene and (b) each carbon atom in A² which isconnected to E¹ and E² in which E² is O— or —S(O)_(m)— does not possessdouble bond),

[0033] E¹ is —O— or —S—,

[0034] E² is —CH₂—, —O— or —S(O)_(m)—,

[0035] m is 0, 1 or 2,

[0036] each R¹ in (R¹)n independently, is hydrogen, C1-8 alkyl, halogen,C1-4 alkoxy,

[0037] C1-4 alkylthio, nitro, NR⁷R⁸ (in which R⁷ and R⁸ eachindependently, is C1-4 alkyl), cyano, trifluoromethyl,trifluoromethyloxy, carbocyclic ring or heterocyclic ring (in whichcarbocyclic ring and heterocyclic ring may be substituted with the groupselected from C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl),

[0038] R² is hydrogen, C1-8 alkyl, halogen, C1-4 alkoxy, C1-4 alkylthio,nitro, NR⁷R⁸ (in which R⁷ and R⁸ each independently, is C1-4 alkyl),cyano, trifluoromethyl or trifluoromethyloxy,

[0039] R³ and R⁴ each independently, is hydrogen or C1-4 alkyl or R³ andR⁴ taken together with carbon atom to which is attached represents C3-7cycloalkylene,

[0040] R⁵ is —COOR⁹ (in which R⁹ is hydrogen or C1-4 alkyl) orheterocyclic ring which is equivalent to carboxylic acid,

[0041]  each independently, is carbocyclic ring or heterocyclic ring and

[0042]  n is 1-3)

[0043]  or non-toxic salt thereof, or hydrate thereof,

[0044] (2) a peroxisome proliferator activated receptor regulatorcomprising, as an active ingredient, a compound of the formula (I) ornon-toxic salt thereof, or hydrate thereof, and

[0045] (3) a process for producing a compound of the formula (I).

DETAILED EXPLANATION

[0046] Unless otherwise specified, all isomers are included in thepresent invention. For example, alkyl, alkoxy, alkylthio, alkylene,alkenylene and alkynylene group includes straight or branched ones. Inaddition, isomers on double bond, ring, fused ring (E-, Z-, cis-,trans-isomer), isomers generated from asymmetric carbon atom(s) (R—, S—,α-, β-isomer, enantiomer, diastereomer), optically active isomers (D-,L-, d-, I-isomer), polar compounds generated by chromatographicseparation (more polar compound, less polar compound), equilibriumcompounds, mixtures thereof at voluntary ratios and racemic mixtures arealso included in the present invention.

[0047] In the formula (I), C1-4 alkylene represented by A¹ meansmethylene, ethylene, trimethylene, tetramethylene and isomers thereof.

[0048] In the formula (I), C1-4 alkyl represented by R³, R⁴, R⁷, R⁸ andR⁹ or C1-4 alkyl as a substituent of carbocyclic ring or heterocyclicring represented by R¹ means methyl, ethyl, propyl, butyl and isomersthereof.

[0049] In the formula (I), C1-8 alkyl represented by R¹ and R² meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomersthereof.

[0050] In the formula (I), C1-4 alkoxy represented by R¹ and R² or C1-4alkoxy as a substituent of carbocyclic ring or heterocyclic ringrepresented by R¹ means methoxy, ethoxy, propoxy, butoxy and isomersthereof.

[0051] In the formula (I), C1-4 alkylthio represented by R¹ and R² meansmethylthio, ethylthio, propylthio, butylthio and isomers thereof.

[0052] In the formula (I), C2-8 alkylene represented by A² meansethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof.

[0053] In the formula (I), C3-8 alkenylene represented by A² means1-propynylene, 1-butenylene, 2-butenylene, 2-methyl-2-butenylene,3-methyl-2-butenylene, pentenylene, hexenylene, heptenylene, octenyleneand isomers thereof.

[0054] In the formula (I), C3-8 alkynylene represented by A² means1-propynylene, 1-butynylene, 2-butynylene, pentynylene, hexynylene,heptynylene, octynylene and isomers thereof.

[0055] In the formula (I), halogen represented by R¹ and R² or halogenas a substituent of carbocyclic ring or heterocyclic ring represented byR¹ means fluoride, chloride, bromide and iodide.

[0056] In the formula (I), C3-7 cycloalkylene represented by R³ and R⁴taken together with carbon atom to which is attached meanscyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene andcycloheptylene.

[0057] In the formula (I), heterocyclic ring which is equivalent to thecarboxylic acid represented by R⁵ includes, for example,1H-tetrazol-5-yl, thiazolidine-2,4-dion-5-yl, oxazolidin-2,4-dion-5-yl,isooxazolidin-3, 5-dion-4-yl, 1,2,4-oxadiazolidin-3,5dion-2-yl etc.shown by the following structure:

[0058] but does not limit to the said group.

[0059] In the formula (I), carbocyclic ring represented by R¹,

[0060] means C3-10 mono- or bi-cyclic carbocyclic ring and bicyclocarbocyclic ring. For example, C3-10 mono- or bi-cyclic carbocyclic ringand bicyclo carbocyclic ring mean cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cyclopentadien, cyclohexadien,benzene, pentalene, indene, naphthalene, azulene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, indane (dihydroindene),perhydroindene, bicyclopentane, bicyclohexane, bicycloheptane([2.2.1]bicycloheptane), bicyclooctane, bicyclononane, bicyclodecane,adamantane etc.

[0061] In the formula (I), heterocyclic ring represented by R¹,

[0062] means 5-15-membered mono- or bi-cyclic heterocyclic ringcontaining 1-3 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfuratom which is unsaturated or saturated partially or fully. For example,5-15-membered mono- or bi-cyclic heterocyclic ring containing 1-3nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom which isunsaturated or saturated partially or fully includes pyroline,pyrrolidine, imidazoline, imidazolidine, pyrazoline, piperazolidine,piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine,tetrahydropyridazine, hexahydropyridazine, hexahydroazepine,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran),tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole,tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole,dihydrothiazole, tetrahydrothiazole, dihydroisothiazole,tetraisothiazole, morpholine, thiomorpholine, indoline, isoindoline,dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine,tetrahydronaphthyl idine, perhydronaphthylidine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzooxazole,perhydrobenzooxazole, dihydrobenzoth iazole, perhydrobenzoth iazole,dihydrobenzoimidazole, perhydrobenzoimidazole, dihydrobenzooxazine,dioxaindane (1,3-dioxaindane), benzodioxane, quinuclidine, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,pyridazine, azepine, diazepine, furan, pyran, oxepine, oxazepine,thiophene, thiain (thiopyran), thiepine, oxazole, isooxazole, thiazole,isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine,thiadiazole, thiazine, thiadiazine, thiaazepine, thiaazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline,benzooxazole, benzothiazole, benzoimidazole, oxatetrahydrofuran,imidazopyridine, benzotriazole etc.

[0063] In the formula (I), A¹ is preferably, every group and morepreferably methylene or ethylene.

[0064] In the formula (I), A² is preferably, every group, morepreferably C4-6 alkylene, C4-6 alkenylene, C4-6 alkynylene, much morepreferably tetramethylene, 2-butenylene, 2-butynylene, or the said groupwhich is substituted with 1-2 of methyl, and most preferably2-butynylene.

[0065] In the formula (I), E¹ is preferably, every group and morepreferably —O—.

[0066] In the formula (I), E² is preferably, every group and morepreferably —S— or —CH₂—.

[0067] In the formula (I), R⁵ is preferably, every group, morepreferably —COOR⁹, 1H-tetrazol-5-yl, or thiazolidine-2,4-dion-5-yl andmost preferably —COOR⁹.

[0068] In the formula (I),

[0069] is preferably, every group, more preferably C5-6 mono-cycliccarbocyclic ring, or 5-6-membered mono-cyclic heterocyclic ringcontaining 1-2 nitrogen atom(s), one oxygen atom and/or one sulfur atom,much more preferably

[0070] and most preferably

[0071] In the formula (I),

[0072] is preferably, every group, more preferably C5-10 mono- orbi-cyclic carbocyclic ring, or 5-10-membered mono- or bi-cyclicheterocyclic ring containing 1-2 nitrogen atom(s), 1-2 oxygen atom(s)and/or one sulfur atom which is unsaturated or saturated partially orfully, and most preferably cyclopentane, cyclohexane, cycloheptane,benzene, furan, thiophene, pyridine, quinoline, dioxaindane (forexample, 1,3-dioxaindane).

[0073] In the present invention, PPAR regulator includes all theregulators of PPARα, γ, δ, α+γ, α+δ, γ+δ and α+γ+δ. Preferableregulatory fashion is, PPARα regulator, PPARγ regulator, PPARδregulator, PPARα+γ regulator, PPARα+δ regulator, more preferably PPARα+γregulator.

[0074] PPAR regulator also includes PPAR agonist and PPAR antagonist,preferably PPAR agonist, more preferably PPARα agonist, PPARγ agonist,PPARδ agonist, PPARα+γ agonist or PPARα+δ agonist, particularlypreferably PPARα+γ agonist.

[0075] Among the compounds of the formula (I), compounds of the formula(Ia)

[0076] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib)

[0077] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic)

[0078] (wherein, all the symbols are the same meanings as definedhereinbefore), non-toxic salt thereof, or hydrate thereof arepreferable.

[0079] The compounds of the formula (Ia-A)

[0080] (wherein, A²⁻³ is C3-8 alkynylene and the other symbols are thesame meanings as defined hereinbefore), compounds of the formula (Ia-B)

[0081] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-C)

[0082] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-A)

[0083] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-B)

[0084] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-C)

[0085] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-A)

[0086] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-B)

[0087] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-C)

[0088] (wherein, all the symbols are the same meanings as definedhereinbefore), non-toxic salt thereof, or hydrate thereof are morepreferable.

[0089] The compounds of the formula (Ia-1)

[0090] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-2)

[0091] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-3)

[0092] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-4)

[0093] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-5)

[0094] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ia-6)

[0095] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-1)

[0096] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-2)

[0097] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ib-3)

[0098] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-1)

[0099] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-2)

[0100] (wherein, all the symbols are the same meanings as definedhereinbefore), compounds of the formula (Ic-3)

[0101] (wherein, all the symbols are the same meanings as definedhereinbefore), non-toxic salt thereof, or hydrate thereof are mostpreferable.

[0102] Concrete compounds of the present invention are, for example, thecompounds shown in the following Tables 1-16, non-toxic salts thereofand hydrates thereof, and compounds described in Example hereafter.

[0103] In each Table, Me is methyl and the other symbols are the samemeanings as defined hereinbefore. TABLE 1 (Ia-1-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0104] TABLE 2 (Ia-1-2) No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0105] TABLE 3 (Ia-2-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0106] TABLE 4 (Ia-3-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0107] TABLE 5 (Ia-4-1)

No. (R¹)_(n) A² 1 H

2 4-Me

3 4-F

4 4-Cl

5 4-CF₃

6 4-OMe

7 4-NO₂

8 2,2-di-F

9

10 4-Me

11 4-F

12 4-Cl

13 4-CF₃

14 4-OMe

15 4-NO₂

16 2,2-di-F

17 H

18 4-Me

19 4-F

20 4-Cl

21 4-CF₃

22 4-OMe

23 4-NO₂

24 2,2-di-F

[0108] TABLE 6 (Ia-4-2)

No. (R¹)_(n) A² 1 H

2 4-Me

3 4-F

4 4-Cl

5 4-CF₃

6 4-OMe

7 4-NO₂

8 2,2-di-F

9 H

10 4-Me

11 4-F

12 4-Cl

13 4-CF₃

14 4-OMe

15 4-NO₂

16 2,2-di-F

17 H

18 4-Me

19 4-F

20 4-Cl

21 4-CF₃

22 4-OMe

23 4-NO₂

24 2,2-di-F

[0109] TABLE 7 (Ia-5-1)

No. (R¹)_(n) A² 1 H

2 4-Me

3 4-F

4 4-Cl

5 4-CF₃

6 4-OMe

7 4-NO₂

8 2,2-di-F

9 H

10 4-Me

11 4-F

12 4-Cl

13 4-CF₃

14 4-OMe

15 4-NO₂

16 2,2-di-F

17 H

18 4-Me

19 4-F

20 4-Cl

21 4-CF₃

22 4-OMe

23 4-NO₂

24 2,2-di-F

[0110] TABLE 8 (Ia-6-1)

No. (R¹)_(n) A² 1 H

2 4-Me

3 4-F

4 4-Cl

5 4-CF₃

6 4-OMe

7 4-NO₂

8 2,2-di-F

9 H

10 4-Me

11 4-F

12 4-Cl

13 4-CF₃

14 4-OMe

15 4-NO₂

16 2,2-di-F

17 H

18 4-Me

19 4-F

20 4-Cl

21 4-CF₃

22 4-OMe

23 4-NO₂

24 2,2-di-F

[0111] TABLE 9 (Ib-1-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0112] TABLE 10 (Ib-1-2)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 CI

19 CF₃

20 OMe

21 NO₂

[0113] TABLE 11 (Ib-2-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0114] TABLE 12 (Ib-3-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0115] TABLE 13 (Ic-1-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0116] TABLE 14 (Ic-1-2)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0117] TABLE 15 (Ic-2-1)

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

[0118] TABLE 16

No. R¹ A² 1 H

2 Me

3 F

4 Cl

5 CF₃

6 OMe

7 NO₂

8 H

9 Me

10 F

11 Cl

12 CF₃

13 OMe

14 NO₂

15 H

16 Me

17 F

18 Cl

19 CF₃

20 OMe

21 NO₂

Process for Producing the Compounds of the Present Invention

[0119] (a) Compounds of the formula (I) wherein E² is —O— or —S— and R⁵is —COOR⁹⁻¹ (in which R⁹⁻¹ is C1-4 alkyl) or heterocyclic ring which isequivalent to carboxylic acid, i.e., the compounds of the formula (I-A)

[0120] (wherein, E²⁻¹ is —O— or —S—, R⁵⁻¹ is —COOR⁹⁻¹ (in which R⁹⁻¹ isC1-4 alkyl) or heterocyclic ring which is equivalent to carboxylic acidand the other symbols are the same meanings as defined hereinbefore)

[0121] may be prepared by reacting the compounds of the formula (II)

[0122] (wherein, R¹⁰ is methanesulfonyloxy or halogen and the othersymbols are the same meanings as defined hereinbefore)

[0123] and the compounds of the formula (III)

[0124] (wherein, E^(2-1a) is —OH or —SH and the other symbols are thesame meanings as defined hereinbefore).

[0125] The said reaction may be carried out by known methods. It may becarried out, for example, in an organic solvent (tetrahydrofuran (THF),diethylether, methylene chloride, chloroform, tetrachloromethane,pentane, hexane, benzene, toluene, dimethylformamide (DMF),dimethylsulfoxide (DMSO), hexamethylphosphamide (HMPA), acetonitrileetc.) in the presence of base (sodium hydroxide, potassium carbonate,triethylamine, pyridine, sodium iodide, potassium iodide, cesiumcarbonate etc.) at 0-80° C.

[0126] (b) Compounds of the formula (I) wherein E² is —CH₂— and R⁵ is—COOR⁹⁻¹ (in which R⁹⁻¹ is C1-4 alkyl) or heterocyclic ring which isequivalent to carboxylic acid, i.e., the compounds of the formula (I-B)

[0127] (wherein, E²⁻² is —CH₂— and the other symbols are the samemeanings as defined hereinbefore)

[0128] may be prepared by reacting the compounds of the formula (IV)

[0129] (wherein, all the symbols are the same meanings as definedhereinbefore) and the compounds of the formula (V-1)

[0130] (wherein, E¹⁻¹ is —OH or —SH and the other symbols are the samemeanings as defined hereinbefore)

[0131] or by reacting the compounds of the formula (VII)

[0132] (wherein, all the symbols are the same meanings as definedhereinbefore) and the compounds of the formula (V-2)

[0133] (wherein, all the symbols are the same meanings as definedhereinbefore).

[0134] The said reaction may be carried out by known methods. It may becarried out, for example, in an organic solvent (THF, diethylether,methylene chloride, chloroform, tetrachloromethane, pentane, hexane,benzene, toluene, DMF, DMSO, HMPA, or mixture solvent thereof etc.) inthe presence of base (sodium hydroxide, potassium carbonate,triethylamine, pyridine, sodium iodide, cesium carbonate etc.) at 0-80°C.

[0135] (c) Compounds of the formula (I) wherein E² is —O—, —S—, or —CH₂—and R⁵ is —COOH, i.e., the compounds of the formula (I-C)

[0136] (wherein, E²⁻³ is —O—, —S—, or —CH₂— and the other symbols arethe same meanings as defined hereinbefore)

[0137] may be prepared by hydrolysis of the compounds of the formula(I-A) wherein R⁵⁻¹ is —COOR⁹⁻¹, i.e., the compounds of the formula(I-A-1)

[0138] (wherein, all the symbols are the same meanings as definedhereinbefore) or the compounds of the formula (I-B) wherein R⁵⁻¹ is—COOR⁹⁻¹, i.e., the compounds of the formula (I-B-1)

[0139] (wherein, all the symbols are the same meanings as definedhereinbefore).

[0140] In addition, compounds of the formula (I-C) wherein A² is C3-8alkynylene and E² is —CH₂—, i.e., the compounds of the formula (I-C-1)

[0141] (wherein, A²⁻³ is C3-8 alkynylene and the other symbols are thesame meanings as defined hereinbefore)

[0142] may be prepared by hydrolysis of the compounds of the formula(XII)

[0143] (wherein, R⁶ is a carboxyl group which is protected (for example,4-methyl-2,6,7-trioxabicyclo[3.2.2]octan-1yl etc.) and the other symbolsare the same meanings as defined hereinbefore).

[0144] The said hydrolysis may be carried out by known methods. It maybe carried out, for example,

[0145] (1) in an organic solvent admissible with water (THF, dioxane,ethanol, methanol etc.) or mixture solvent thereof, using an aqueoussolution of alkali (potassium hydroxide, sodium hydroxide, lithiumhydroxide, potassium carbonate, sodium carbonate etc.),

[0146] (2) in alkanol (methanol, ethanol etc.), using the above alkaliunder an anhydrous condition or

[0147] (3) in an organic solvent (THF, dioxane, ethanol, methanol etc.)or mixture solvent thereof, using acid (hydrochloric acid, sulfuric acidetc.) and alkali (sodium hydroxide, potassium hydroxide etc.).

[0148] These reactions may be carried out at 0-100° C. normaly. Inaddition, the said hydrolysis may be carried out

[0149] (4) in mixture solvent of an organic solvent admissible withwater (ethanol, dimethylsulfoxide etc.) and water, in the presence orabsence of buffer, using enzyme to decompose ester (esterase, lipaseetc.) at 0-50° C.

[0150] (d) Compounds of the formula (I) wherein E² is —O—, —S— or —CH₂—and heterocyclic ring represented by R⁵ which is equivalent tocarboxylic acid is 1H-tetrazol-5-yl, i.e., the compounds of the formula(I-D)

[0151] (wherein, all the symbols are the same meanings as definedhereinbefore) may be also prepared by reacting the compounds of theformula (VI)

[0152] (wherein, all the symbols are the same meanings as definedhereinbefore) in an alkaline condition.

[0153] The said reaction may be carried out by known methods. It may becarried out, for example, in an organic solvent admissible with water(methanol, ethanol, dioxane etc.), using alkali (potassium hydroxide,sodium hydroxide, potassium carbonate, sodium carbonate etc.) at 0-50°C.

[0154] (e) Compounds of the formula (I) wherein m is 1 or 2, that is tosay, E² is —SO— or —SO₂—, i.e., the compounds of the formula (I-E)

[0155] (wherein, E²⁻⁴ is —S(O)_(mm)— (in which mm is 1 or 2) and theother symbols are the same meanings as defined hereinbefore)

[0156] may be prepared by oxidizing the compounds of the formula (I-A)wherein E²⁻¹ is —S— or the compounds of the formula (I-C) or (I-D)wherein each E²⁻³ is —S—.

[0157] In addition, the compounds of the formula (I-E) wherein E²⁻⁴ is—SO₂— may be also parepared by oxidizing the compounds of the formula(I-E) wherein E²⁻⁴ is —SO—.

[0158] The said oxidizing may be carried out by known methods. It may becarried out, for example, in an organic solvent (THF, methylenechloride, chloroform etc.), using a necessaryl amount of oxidizing agent(perhydrogen oxide, sodium periodate, acyl nitrite, sodium perboronate,peracid (e.g., 3-chloroperbenzoic acid, peracetic acid, OXONE (trademark)) etc.) at 0-50° C.

[0159] The compounds of the formulae (II), (III), (IV), (V-1), (V-2),(VI), (VII) and (XII) are known per se or may be prepared by knownmethods.

[0160] For example, among the compounds of the formula (III),mercaptoacetic acid methyl ester (thioglycolic acid methyl) has beenmarketed.

[0161] For example, the compounds of the formulae (II), (IV), (VI) and(XII) may be prepared according to the following Reaction Schemes 1-4.

[0162] In each Reaction Scheme, the abbrevation and symbols are as thefollowing meanings and the other symbols are the same meanings asdefined hereinbefore.

[0163] THP: tetrahydropyran-2-yl,

[0164] A²⁻¹: C3-8 alkenylene or C3-8 alkynylene,

[0165] X: halogen,

[0166] A²⁻²: C2-8 alkylene,

[0167] EDC HCl: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride,

[0168] HOBt: 1-hydroxybenzotriazole,

[0169] Et₃N: triethylamine,

[0170] TMSN₃: trimethylsilylazide.

[0171] In the said Reaction Schemes, the compounds of the formula (VII),(VIII-1), (VIII-2), (XI) and (XVII) are known per se or may be preparedby known methods.

[0172] The reactions described in the above-mentioned Schemes may becarried out by known methods.

[0173] In the present invention, the other starting materials and eachreagent are known per se or may be prepared by known methods.

[0174] In each reaction in the present specification, products may bepurified by a conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction or after a series ofreactions.

[0175] All the non-toxic salts are also included in the presentinvention. For example, the compounds of the formula (I) of the presentinvention may be converted into the corresponding salts by knownmethods. Non-toxic and water-soluble salts are preferable. Suitablesalts, for example, are follows:

[0176] salts of alkaline metals (potassium, sodium etc.), salts ofalkaline earth metals (calcium, magnesium etc.), ammonium salts, saltsof pharmaceutically acceptable organic amines (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,cyclohexylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine etc.).

[0177] The compounds of the formula (I) of the present invention may beconverted into the corresponding acid additional salts by methods knownper se. Non-toxic and water-soluble acid addition salts are preferable.Suitable acid addition salts, for example, are salts of inorganic acids,e.g., hydrochloride, hydrobromide, sulphate, phosphate, nitrate etc., orsalts of organic acids, e.g., acetate, trifluoroacetate, lactate,tartarate, oxalate, fumarate, maleate, citrate, benzoate,methanesulphonate, ethanesulphonate, benzenesulphonate,toluenesulphonate, isethioate, glucuronate, gluconate etc.

[0178] The compounds of the formula (I) of the present invention orsalts thereof may be converted into hydrate thereof by methods known perse.

Pharmacological Activity

[0179] It was confirmed that a compound of the present invention offormula (I) has PPAR regulating activities by the following experiments.

Measurement of PPARα Agonistic and PPARγ Agonistic Activities (1)Preparation of Materials in Luciferase Assay using Human PPARα or δ

[0180] The whole operations were carried out by the basic methods ingene engineering techniques and the conventional methods in yeastOne-hybrid or Two-hybrid system.

[0181] As a luciferase gene expression vector under the control ofthymidine kinase (TK) promotor, luciferase structural gene was excisedfrom PicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No.309-04821), to prepare luciferase gene expression vector pTK-Luc. underthe control of TK promotor (−105/+51) as a minimum essential promotoractivity from pTKβ having TK promotor (Chrontech Inc., catalogue No.6179-1). In the upper stream of TK promotor, four times repeated UASsequence was inserted, which is the response element of Gal4 protein, abasic transcription factor in yeast, to construct 4×UAS-TK-Luc. asreporter gene. The following is the enhancer sequence used (Sequence No.1).

[0182] Sequence No. 1: Enhancer sequence repeating Gal4 response elementfour-times tandemly.

[0183] 5′-T(CGACGGAGTACTGTCCTCCG)×4 AGCT-3′

[0184] A vector was prepared as described hereafter which expresseschimeric receptor protein wherein in carboxyl terminus of yeast Gal4protein DNA binding domain was fused to ligand binding domain of humanPPARα or γ. That is to say, PicaGene Basic Vector 2 (trade name, ToyoInk Inc., catalogue No. 309-04821) was used as a basic expressionvector, the structural gene was exchanged for that of chimeric receptorprotein, while promotor and enhancer domains were kept as they were.

[0185] DNA encoding a fused protein composed of Gal4 DNA binding domain,the 1st to 147th amino acid sequence linked to the ligand binding domainof human PPARα or γ in frame was inserted to the downstream ofpromotor/enhancer in PicaGene Basic Vector 2 (trade name, Toyo Ink Inc.,catalogue No. 309-04821). Here the DNA was aligned as follows; in theamino terminus of human PPARα or γ ligand binding domain, nucleartranslocation signal originated from SV-40 T-antigen, Ala Pro Lys LysLys Arg Lys Val Gly (sequence No. 2) was added to make fusion proteinlocalizing intranuclearly. On the other hand, in the carboxy terminus ofthem, influenza hemagglutinin epitope, Tyr Pro Tyr Asp Val Pro Asp TyrAla (sequence No. 3) and stop codon for translation was added in thisorder, to detect an expressed fused protein tagged epitope sequence.

[0186] According to the comparison of human PPAR structures described inthe literatures by R. Mukherjee at al. (See J. Steroid Biochem. Molec.Biol., 51, 157 (1994)), M. E. Green et al., (See Gene Expression., 4,281 (1995)), A. Elbrecht et al. (See Biochem Biophys. Res. Commun., 224,431 (1996)) or A. Schmidt et al. (See Mol. Endocrinology., 6, 1634(1992)), the portion of structural gene used as ligand binding domain ofhuman PPARα or γ was DNA encoding the following peptide:

[0187] human PPARα ligand binding domain: Ser¹⁶⁷-Tyr⁴⁶⁸

[0188] human PPARγ ligand binding domain: Ser¹⁷⁶-Tyr⁴⁷⁸

[0189] (each human PPARγ1 ligand binding domain and human PPARγ2 ligandbinding domain is Ser²⁰⁴-Tyr⁵⁰⁶ which is identical sequence each other).

[0190] In order to measure basal level of transcription, an expressionvector containing DNA binding domain of Gal4 protein lacking in PPARligand binding domain, which is exclusively encoding the 1st to 147thamino acid sequence in Gal4 protein was also prepared.

(2) Luciferase Assay using Human PPARα or γ

[0191] CV-1 cells used as host cells were cultured by a conventionaltechnique. That is to say, Dulbecco's modified Eagle medium (DMEM)supplemented 10% bovine fetal serum (GIBCO BRL Inc., catalogue No.26140-061) and 50 U/ml of penicillin G and 50 μg/ml of streptomycinsulfate were used to culture CV-1 cells under the atmosphere of 5%carbon dioxide gas at 37° C.

[0192] 2×10⁶ cells were seeded in a 10 cm dish, and once washed with themedium without serum, followed by addition of the medium (10 ml)thereto. Reporter gene (10 μg), Gal4-PPAR expression vector (0.5 μg) and50 μl of LipofectAMINE (GIBRO BRL Inc., catalogue No. 18324-012) werewell mixed and added to the culture to introduce these DNAs into thehost cells. They were cultured at 37 ° C. for 5˜6 hours, and thereto wasadded 10 ml of medium containing 20% of dialyzed bovine fetal serum(GIBRO BRL Inc., catalogue No.26300-061), and then cultured at 37° C.overnight. The cells were dispersed by trypsin, and they were againseeded in 96-well plates in a density of 8000 cells/100 ml of DMEM-10%dialyzed serum/well. Several hours after the cultivation, when cellswere attached to the plastic ware, then 100 μl of DMEM-10% dialyzedserum containing the compounds of the present invention, whoseconcentration is twice as high as the final concentration of them, wasadded thereto. The culture was settled at 37° C. for 42 hours and thecells were dissolved to measure luciferase activity according tomanufacturer's instruction.

[0193] As to PPARα agonistic activity, the relative activity of thecompounds of the present invention (10 μM) was shown in Table 17, underthe condition that luciferase activity was defined as 1.0 in case ofcarbacyclin (10 μM) as a positive control compound, which could activatetranscription of luciferase gene significantly to PPARα (See Eur. J.Biochem., 233, 242 (1996); Genes & Development., 10, 974 (1996)).

[0194] As to PPARγ agonistic activity, the relative activity of thecompounds of the present invention (10 μM) was shown in Table 18, underthe condition that luciferase activity was defined as 1.0 in case oftroglitazone (10 μM) as a positive control compound, which couldactivate transcription of luciferase gene significantly to PPARγ (SeeCell., 83, 863 (1995); Endocrinology., 137, 4189 (1996) and J. Med.Chem., 39, 665 (1996)) and has been already launched as hypoglycemicagent.

[0195] Furthermore, assay of each compound was carried out three timesto examine its reproducibility and to confirm the dose dependentactivity. TABLE 17 Relative Activity to a positive control compoundExample Nos. (carbacyclin = 1) Example 5 2.8 Example 5 (2) 2.9 Example 5(8) 2.2 Example 5 (10) 1.5 Example 5 (11) 1.7

[0196] TABLE 18 Relative Activity to a positive control compound ExampleNos. (troglitazone = 1) Example 5 2.6 Example 5 (2) 2.6 Example 5 (8)2.3 Example 5 (10) 2.7 Example 5 (11) 2.3

Hypoglycemic and Hypolipidemic Effects

[0197] Male, 7-weeks old KKAy/Ta mice weighed from 35 to 40 g (five miceper group) were pre-breaded for approximately one week and acclimatizedfor three days on milled diet. On the first day of the experiment (Day0), mice were divided into some groups according to weight, plasmaglucose and triglyceride (TG) levels to minimize the differences amonggroups. From the next day for two days they were given compounds by foodmixture containing 0.03% (w/w) of the compound of the present inventionor by milled diet only. At 13:00 of the third day, blood samples werecollected to measure glucose and TG levels. The results are shown inTable 19. Additionally, there was no significant difference in the foodintake between control group (milled diet only) and compounds-treatedgroup (milled diet containing 0.03% compounds). TABLE 19 glycemic level(mg/dl) TG level (mg/dl) Example Nos. on Day 3 on Day 3 Control 638 ±63  523 ± 144 food containing compound 339 ± 74* 111 ± 38* of Example 5(10) at 44.7 mg/kg/day (converted) food containing compound 306 ± 72*140 ± 75* of Example 5 (11) at 43.9 mg/kg/day (converted)

Hypocholesterolemic and Hypolipidemic Effects

[0198] Male, six-weeks old SD rats (five rats per group) were left totake milled diet and water ad libitum and were acclimatized for 1 week.

[0199] At 9:00 on the first day of the experiment (Day 0), bloodsampling was done from tail vein. The rats were divided into some groupsaccording to body weight, triglyceride (TG), non-esterified fatty acid(NEFA) and total cholesterol (TC) levels to minimize differences of theparameters among the groups. At 17:00 of the day, the compound of thepresent invention dissolved in 0.5% aqueous solution ofcarboxymethylcellulose (CMC) was orally administered, and thereafter,with hypercholesterolemic food (5.5% peanut oil, 1.5% cholesterol and0.5% cholic acid were mixed with milled CRF-1 diet, Charles River Inc.)was given to the rats.

[0200] At 9:00 of the next day, blood sampling was done from tail vein.The lipid levels in blood (TG, NEFA and TC levels) after administrationof the compounds of the present invention were measured. The results areshown in Table 20. There was no significant difference of the foodintake between the control group (provided only 0.5% CMC) and the grouptreated with the compounds of the present invention. TABLE 20 TC levelTG level NEFA levle Example Nos. (mg/dl) (mg/dl) (μEq/l) Control 154 ±8  158 ± 19  537 ± 69 Example 5 (10) 88 ± 6* 95 ± 17* 334 ± 55 Example 5(11) 91 ± 6* 90 ± 14*  227 ± 17*

[0201] The hypoglycemic or hypolipidemic effects observed in KKAy miceimply the possibility of preventives and/or remedies for diabetes andhyperlipidemia etc. Cholesterol-lowering and free fatty acid-loweringeffects observed in high cholesterol diet-fed rats imply that thecompounds of the present invention are useful as preventives and/orremedies of atherosclerosis etc.

[0202] The compounds of the present invention possess the hypoglycemicor hypolipidemic (TG, NEFA) effects as well as cholesterol-loweringeffect, so they are expected to be more useful to compare with themarketed hypoglycemic or hypolipidemic drugs.

[0203] In addition, it has been known that hyperlipidemia, obesity ordiabetes are one of cause of uncondition in liver function andhyperlipid in liver. Therefore, the compounds of the present inventionare expected to be the drugs to improve liver function which has notbeen marketed.

Industrial Applicability Effect

[0204] The compounds of the formula (I) of the present invention,non-toxic salts thereof, acid addition salts thereof and hydratesthereof have PPAR regulating effect, and therefore are expected to beapplied as hypoglycemic agents, hypolipidemic agents, preventives and/orremedies for diseases associated with metabolic disorders (diabetes,obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemiaetc.), hyperlipidemia, atherosclerosis, hypertension, circulatorydiseases, overeating, coronary heart diseases etc., HDLcholesterol-elevating agents, LDL cholesterol and/or VLDLcholesterol-lowering agents and agents for relieving risk factors ofdiabetes or syndrome X.

[0205] The compounds of formula (I) of the present invention, non-toxicsalts thereof, acid addition salts thereof and hydrates thereof haveparticularly PPAR α agonist and/or PPARγ agonist effect, and thereforeare thought to be useful as hypoglycemic agents, hypolipidemic agents,preventives and/or remedies for diseases associated with metabolicdisorders (diabetes, obesity, syndrome X, hypercholesterolemia,hyperlipoproteinemia etc.), hyperlipidemia, atherosclerosis,hypertension, circulatory diseases and overeating etc. Since they areexpected to have HDL cholesterol-elevating effect, LDL cholesteroland/or VLDL cholesterol-lowering effect, inhibition of progress ofatherosclerosis and its treatment, and inhibitory effect againstobesity, they are also expected to be useful for the treatment and/orprevention of diabetes as hypoglycemic agents, for the amelioration ofhypertension, for the relief from risk factors of syndrome X, and aspreventives against occurrence of coronary heart diseases.

Toxicity

[0206] The toxicity of the compounds of the present invention is verylow and therefore, it may be considered that the compounds of thepresent invention are safe for pharmaceutical use.

Application for Pharmaceuticals

[0207] For the purpose above described, the compounds of the presentinvention of the formula (I), non-toxic salts and acid addition saltsthereof and hydrates thereof may be normally administered systemicallyor locally, usually by oral or parenteral administration.

[0208] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 0.1mg and 100 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1 and 24hrs. per day into vein.

[0209] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases in which doses lower than orgreater than the ranges specified above may be used.

[0210] The compounds of the present invention may be administered asinner solid compositions or inner liquid compositions for oraladministration, or as injections, liniments or suppositories etc. forparenteral administration.

[0211] Inner solid compositions for oral administration includecompressed tablets, pills, capsules, dispersible powders and granulesetc. Capsules contain hard capsules and soft capsules.

[0212] In such inner solid compositions, one or more of the activecompound(s) is or are, admixed with at least one inert diluent (lactose,mannitol, glucose, microcrystalline cellulose, starch etc.), connectingagents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesiummetasilicate aluminate etc.), disintegrating agents (cellulose calciumglycolate etc.), lubricating agents (magnesium stearate etc.),stabilizing agents, assisting agents for dissolving (glutamic acid,asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods.The pharmaceuticals may, if desired, be coated with material such assugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulosephthalate etc., or be coated with two or more films. And further,coating may include containment within capsules of absorbable materialssuch as gelatin.

[0213] Inner liquid compositions for oral administration includepharmaceutically-acceptable water-agents, suspensions, emulsions, syrupsand elixirs etc. In such liquid compositions, one or more of the activecompound(s) is or are comprised in inert diluent(s) commonly used in theart (purified water, ethanol or mixture thereof etc.). Besides inertdiluents, such compositions may also comprise adjuvants such as wettingagents, suspending agents, emulsifying agents, sweetening agents,flavouring agents, perfuming agents, preserving agents and buffer agentsetc.

[0214] Injections for parenteral administration include solutions,suspensions and emulsions and solid injections which are dissolved orsuspended in solvent when it is used. One or more active compound(s) isor are dissolved, suspended or emulsified in a solvent when suchcompositions are used. Aqueous solutions or suspensions includedistilled water for injection and physiological salt solution, plantoil, propylene glycol, polyethylene glycol and alcohol such as ethanoletc., and mixture thereof. Such compositions may comprise additionaldiluents such as stabilizing agent, assisting agents for dissolving(glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark)etc.), suspending agents, emulsifying agents, dispersing agents, bufferagents, preserving agents etc. They may be sterilized for example, byfiltration through a bacteria-retaining filter, by incorporation ofsterilizing agents in the compositions or by irradiation. They may alsobe manufactured in the form of sterile solid compositions and which canbe dissolved in sterile water or some other sterile diluent forinjection immediately before use.

[0215] Other compositions for parenteral administration include liquidsfor external use, ointments, endermic liniments, aerosols, spraycompositions, suppositories and pessaries for vaginal administrationetc. which comprise one or more of the active compound(s) and may beprepared by known methods.

[0216] Spray compositions may comprise additional substances other thaninert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate,stabilizing agents to give isotonicity, isotonic buffer such as sodiumchloride, sodium citrate, citric acid. For preparation of such spraycompositions, for example, the method described in the U.S. Pat. Nos.2,868,691 or 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

[0217] The following Reference Examples and Examples are intended toillustrate, but do not limit the present invention.

[0218] The solvents in parenthesis show the developing or elutingsolvents and the ratios of the solvents used are by volume inchromatographic separations and TLC.

[0219] The solvents in parentheses in NMR show the solvents used formeasurement.

REFERENCE EXAMPLE 1 trans-2-buten-1,4-diol

[0220]

[0221] Fumaric acid diethyl ester (1.72 g) was dissolved into benzene(50 ml). Thereto, diisobutylalminium hydride (53 ml, 0.94 M in hexane)was added at 5-10° C. The mixture was stirred at room temperature for 3hours. To the readction mixture, methanol (6 ml) and water (20 ml) wereadded. The mixture was stirred at room temperature for 1 hour. Theprecipitated solid was filtered by Celite. The filtrate was washed bymethanol. The methanol solution and filtrate were concentrated to obtainthe title compound (0.68 g) having the following physical data.

[0222] TLC: Rf 0.15 (ether); NMR (CDCl₃): δ 5.68 (t, J=2.5 Hz, 2H), 4.64(t, J=5.5 Hz, 2H), 3.92 (m, 4H).

REFERENCE EXAMPLE 2 trans-4-(tetrahydropyran-2-yloxy)-2-buten-1-ol

[0223]

[0224] A compound prepared in Reference Example 1 (650 mg) anddihydropyran (0.68 ml) were dissolved into methylene chloride (20 ml).Thereto, pyridinium p-toluenesulfonate (175 mg, abbreviated as PPTS) wasadded at 0° C. The mixture was stirred at room temperature overnight andadded to a cold aqueous saturated solution of sodium chloride. Themixture was extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedwith silica gel column chromatography (hexane:ethyl acetate=2:1→3:2) toobtain the title compound (346 mg) having the following physical data.

[0225] TLC: Rf 0.35 (ethyl acetate:hexane=1:1); NMR (CDCl₃): δ 5.94 (m,1H), 5.83 (m, 1H), 4.66 (t, J=3.5 Hz,1H), 4.27 (m, 1H), 4.20-4.15 (m,2H), 3.99 (m, 1H), 3.88 (m, 1H), 3.52 (m, 1H), 2.00-1.60 (m, 6H).

REFERENCE EXAMPLE 3trans-1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-butene

[0226]

[0227] A compound prepared in Reference Example 2 (326 mg) andtriethylamine (0.39 ml) were dissolved into methylene chloride (10 ml).Thereto, mesyl chloride (263 mg) was added at 0° C. The mixture wasstirred at 0° C. for 1 hour and poured into iced water. The mixture wasextracted with ethyl acetate. The extract was washed by an aqueoussaturated solution of sodium hydrogencarbonate, water and an aqueoussaturated solution of sodium chloride sucessively, dried over anhydrousmagnesium sulfate and concentrated to obtain the title compound (438 mg)having the following physical data.

[0228] TLC: Rf 0.59 (ethyl acetate:hexane=1:1); NMR (CDCl₃): δ 6.03 (m,1H), 5.89 (m, 1H), 4.74 (d, J=5.5 Hz, 2H), 4.64 (t, J=3.0 Hz,1H), 4.29(m, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.02 (s, 3H),2.00-1.60 (m, 6H).

REFERENCE EXAMPLE 4trans-1-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-4-(tetrahydropyran-2-yloxy)-2butene

[0229]

[0230] Sodium hydroxide (115 mg, 60% in oil) was washed by hexane threetimes, and added to tetrahydrofuran (5 ml). Thereto,2-(5-methyl-2-phenyloxazol-4yl)ethanol (488 mg) was added at 0° C. Themixture was stirred for 30 minutes. To the reaction mixture, a solutionof a compound prepared in Reference Example 3 (410 mg) intetrahydrofuran (5 ml) was added. The mixture was stirred overnight. Tothe reaction mixture, iced water was added. The mixture was extractedwith ether. The extract was washed by water and an aqueous saturatedsolution of sodium chloride sucessively, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified with silica gelcolumn chromatography (hexane:ethyl acetate=4:1) to obtain the titlecompound (498 mg) having the following physical data.

[0231] TLC: Rf 0.57 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 5.95-5.70 (m, 2H), 4.64 (t, J=3.5 Hz, 1H), 4.24(m, 1H), 4.05-3.80 (m, 4H), 3.71 (t, J=7.0 Hz, 2H), 3.50 (m, 1H), 2.79(t, J=7.0 Hz, 2H), 2.34 (s, 3H), 2.00-1.45 (m, 6H).

REFERENCE EXAMPLE 5trans-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-buten-1-ol

[0232]

[0233] A compound prepared in Reference Example 4 (332 mg) was dissolvedinto methanol (10 ml). Thereto, p-tolueneshlfonic acid monohydrate (19mg) was added. The mixture was stirred at room temperature for 5 hoursand then poured into iced water. The mixture was extracted with ethylacetate. The extract was washed by water and an aqueous saturatedsolution of sodium chloride sucessively, dried over anhydrous magnesiumsulfate and concentrated to obtain the title compound (255 mg) havingthe following physical data.

[0234] TLC: Rf 0.17 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 5.89 (m, 1H), 5.79 (m, 1H), 4.15 (d, J=4.5 Hz,2H), 4.01 (d, J=4.5 Hz, 2H), 3.71 (t, J=6.0 Hz, 2H), 2.78 (t, J=6.0 Hz,2H), 2.34 (s, 3H).

REFERENCE EXAMPLE 6trans-1-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-4-(methanesulfonyloxy)-2butene

[0235]

[0236] A compound prepared in Reference Example 5 (244 mg) andtriethylamine (0.19 ml) were dissolved into methylene chloride (10 ml).Thereto, methanesulfonyl chloride (126 mg) was added at 0° C. Themixture was stirred at 0° C. for 1 hour. The reaction mixture was addedto iced water and extracted with ethyl acetate. The extract was washedby an aqueous saturated solution of sodium hydrogencarbonate, water andan aqueous saturated solution of sodium chloride sucessively, dried overanhydrous magnesium sulfate and concentrated to obtain the titlecompound (315 mg) having the following physical data.

[0237] TLC: Rf 0.21 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 5.98 (m, 1H), 5.84 (m, 1H), 4.61 (d, J=5.5 Hz,2H), 4.04 (dd, J=4.5, 1.0 Hz, 2H), 3.73 (t, J=7.0 Hz, 2H), 2.99 (s, 3H),2.79 (t, J=7.0 Hz, 2H), 2.35 (s, 3H).

REFERENCE EXAMPLE 7

[0238] 5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylbromide

[0239] The mixture of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (2.03 g),1,5-dibromopentane (4.09 ml), 50% NaOH (4.0 ml) and tributylammoniumbromide (0.1 g) was stirred at room temperature overnight. The reactionmixture was dilluted with ether, washed by water and an aqueoussaturated solution of sodium chloride sucessively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with silicagel column chromatography (hexane:ethyl acetate=10:1→4:1) to obtain thetitle compound (3.45 g) having the following physical data.

[0240] TLC: Rf 0.36 (ethyl acetate:hexane=1:5); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 3.68 (t, J=7.0 Hz, 2H), 3.46 (t, J=6.0 Hz, 2H),3.38 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.34 (s, 3H), 1.82 (m,2H), 1.70-1.40 (m, 4H).

EXAMPLE 1 2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)acetic acid methyl ester

[0241]

[0242] A compound prepared in Reference Example 6 (305 mg),mercaptoacetic acid methyl ester (158 ml) and potassium carbonate (361mg) were dissolved into acetonitrile (5 ml). Thereto, potassium iodide(17 mg) was added at room temperature. The mixture was stirredovernight. The reaction mixture was added to iced water and thenextracted with ether. The extract was washed by 1N—NaOH solution, waterand an aqueous saturated solution of sodium chloride sucessively, driedover anhydrous magnesium sulfate and concentrated to obtain the compound(291 mg) of the present invention having the following physical data.

[0243] TLC: Rf 0.53 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 5.72 (dt, J=15.0, 4.5 Hz,1 H), 5.63 (dt, J=15.0,6.0 Hz, 1H), 4.00 (d, J=4.5 Hz, 2H), 3.71 (s, 3H), 3.70 (t, J=7.0 Hz,2H), 3.24 (d, J=6.0 Hz, 2H), 3.16 (s, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.34(s, 3H).

EXAMPLE 2-EXAMPLE 2(18)

[0244] By the same procedures described in Reference Example 4→ReferenceExample 5→Reference Example 6→Example 1, the following compounds of thepresent invention were obtained.

[0245] In the procedure of Reference Example 4, the following compoundswere used as starting materials.

EXAMPLE 2 cis-1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-buteneand 2-(5-methyl-2-phenyloxazol-4-yl)ethanol EXAMPLE 2(1)1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-phenyloxazol-4-yl)ethanol EXAMPLE 2(2)trans-4-methanesulfonyloxy-1-(tetrahydropyran-2-yloxy)-2-methyl-2-buteneand 2-(5-methyl-2-phenyloxazol-4-yl)ethanol EXAMPLE 2(3)trans-1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-methyl-2-buteneand 2-(5-methyl-2-phenyloxazol-4-yl)ethanol EXAMPLE 2(4)trans-1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-butene and2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(5)trans-1-methanesulfonyloxy-4-(tetrahydropyran-2-yloxy)-2-butene and2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethanol EXAMPLE 2(6)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(7)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethanol EXAMPLE 2(8)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-ethylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(9)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(10)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(11)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(12)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol EXAMPLE 2(13)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethanol EXAMPLE 2(14)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethanol EXAMPLE2(15) 1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethanol EXAMPLE 2(16)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(4-diimethylaminophenyl)oxazol-4-yl)ethanol EXAMPLE 2(17)1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethanol EXAMPLE2(18) 1-bromo-4-(tetrahydropyran-2-yloxy)-2-butyne and2-(5-methyl-2-(2-dimethylaminopyricin-5-yl)oxazol-4-yl)ethanol

[0246] In the procedure of Example 1, the following compounds were usedas starting materials.

EXAMPLE 2-EXAMPLE 2(9), EXAMPLE 2(14) mercaptoacetic acid methyl esterEXAMPLE 2(13) mercaptoacetic acid ethyl ester EXAMPLE 2(10)(2RS)-2-mercaptopropanoic acid ethyl ester EXAMPLE 2(11), EXAMPLE 2(15),EXAMPLE 2(17) 2-mercapto-2-methylpropanoic acid ethyl ester EXAMPLE2(12), EXAMPLE 2(16), EXAMPLE 2(18) (1-mercapto)cyclobutane carboxylicacid ethyl ester EXAMPLE 22-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio) aceticacid methyl ester

[0247]

[0248] TLC: Rf 0.57 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 5.76 (dtt, J=11.0, 6.0, 1.0 Hz, 1H), 5.58 (dtt,J=11.0, 8.0, 1.0 Hz, 1H), 4.07 (dd, J=6.0, 1.0 Hz, 2H), 3.71 (t, J=7.0Hz, 2H), 3.71 (s, 3H), 3.31 (dd, J=8.0, 1.0 Hz, 2H), 3.16 (s, 2H), 2.78(t, J=7.0 Hz, 2H), 2.34 (s, 3H).

EXAMPLE 2(1)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acidmethyl ester

[0249]

[0250] TLC: Rf 0.55 (ethyl acetate:hexane=2:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 4.19 (t, J=2.0 Hz, 2H), 3.78 (t, J=7.0 Hz, 2H),3.73 (s, 3H), 3.44 (t, J=2.0 Hz, 2H), 3.40 (s, 2H), 2.79 (t, J=7.0 Hz,2H), 2.35 (s, 3H).

EXAMPLE 2(2)2-((2E)-2-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester

[0251]

[0252] TLC: Rf 0.54 (hexane:ethyl acetate=2:1); NMR (CDCl₃): δ 8.01-7.93(m, 2H), 7.48-7.36 (m, 3H), 5.50 (dt, J=6.5, 1.2 Hz, 1H), 4.05 (d, J=6.5Hz, 2H), 3.71 (s, 3H), 3.71 (t, J=7.0 Hz, 2H), 3.21 (s, 2H), 3.12 (s,2H), 2.78 (t, J=7.0 Hz, 2H), 2.34 (s, 3H), 1.74 (d, J=1.2 Hz, 3H).

EXAMPLE 2(3)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester

[0253]

[0254] TLC: Rf 0.40 (hexane:ethyl acetate=3:1); NMR (CDCl₃): δ 8.02-7.92(m, 2H), 7.48-7.35 (m, 3H), 5.47 (dt, J=8.0,1.2 Hz, 1H), 3.90 (s, 2H),3.71 (s, 3H), 3.66 (t, J=7.0 Hz, 2H), 3.30 (d, J=8.0 Hz, 2H), 3.16 (s,2H), 2.78 (t, J=7.0 Hz, 2H), 2.35 (s, 3H), 1.66 (d, J=1.2 Hz, 3H).

EXAMPLE 2(4) 2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butenylthio) acetic acid methyl ester

[0255]

[0256] TLC: Rf 0.81 (hexane:ethyl acetate=1:1); NMR (CDCl₃): δ 7.86 (d,J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.56-5.78 (m, 2H), 4.00 (d, J=3.8Hz, 2H), 3.72 (s, 3H), 3.70 (t, J=7.0 Hz, 2H), 3.24 (d, J=5.2 Hz, 2H),3.16 (s, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H).

EXAMPLE 2(5)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2butenylthio)aceticacid methyl ester

[0257]

[0258] TLC: Rf 0.45 (hexane:ethyl acetate=2:1); NMR (CDCl₃): δ 7.51 (dd,J=8.0, 1.7 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.01(s, 2H), 5.57-5.78 (m, 2H), 4.00 (d, J=4.0 Hz, 2H), 3.72 (s, 3H), 3.69(t, J=6.9 Hz, 2H), 3.24 (d, J=5.6 Hz, 2H), 3.16 (s, 2H), 2.75 (t, J=6.9Hz, 2H), 2.32 (s, 3H).

EXAMPLE 2(6) 2-(4-(2-(5-methyl -2-(4-methyl phenyl)oxazol-4-yl)ethoxy)-2-butynylthio)acetic acid methyl ester

[0259]

[0260] TLC: Rf 0.50 (ethyl acetate:hexane=1:2); NMR (CDCl₃): δ 7.85 (d,J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.78 (t,J=7.0 Hz, 2H), 3.73 (s, 3H), 3.44 (t, J=2.0 Hz, 2H), 3.40 (s, 2H), 2.78(t, J=7.0 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H).

EXAMPLE 2(7)2-(4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid methyl ester

[0261]

[0262] TLC: Rf 0.40 (ethyl acetate:hexane=1:2); NMR (CDCl₃): δ 7.81 (dd,J=8.0, 1.5 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.01(s, 2H), 4.20 (t, J=2.0 Hz, 2H), 3.77 (t, J=7.0 Hz, 2H), 3.74 (s, 3H),3.45 (t, J=2.0 Hz, 2H), 3.41 (s, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.32 (s,3H).

EXAMPLE 2(8)2-(4-(2-(5-methyl-2-(4-ethylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)acetic acid methyl ester

[0263]

[0264] TLC: Rf 0.49 (ethyl acetate:hexane=1:2); NMR (CDCl₃): δ 7.88 (d,J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.78 (t,J=7.0 Hz, 2H), 3.73 (s, 3H), 3.44 (t, J=2.0 Hz, 2H), 3.40 (s, 2H), 2.79(t, J=7.0 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J=7.6Hz, 3H).

EXAMPLE 2(9) 2-(4-(2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio) acetic acid methyl ester

[0265]

[0266] TLC: Rf 0.50 (ethyl acetate:hexane=1:2); NMR (CDCl₃): δ 7.88 (d,J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.78 (t,J=7.0 Hz, 2H), 3.73 (s, 3H), 3.44 (t, J=2.0 Hz, 2H), 3.40 (s, 2H), 2.74(t, J=7.0 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.34 (s, 3H), 1.76-1.56 (m,2H), 0.94 (t, J=7.4 Hz, 3H).

EXAMPLE 2(10)(2RS)-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid ethyl ester

[0267]

[0268] TLC: Rf 0.51 (ethyl acetate:hexane=1:2); NMR (CDCl₃): δ 7.86 (d,J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 4.19 (t, J=2.0 Hz, 2H), 4.18 (q,J=7.2 Hz, 2H), 3.78 (t, J=7.0 Hz, 2H), 3.60 (q, J=7.4 Hz, 1H), 3.51 (dt,J=16.6, 2.0 Hz, 1H), 3.34 (dt, J=16.6, 2.0 Hz, 1H), 2.78 (t, J=7.0 Hz,2H), 2.39 (s, 3H), 2.34 (s, 3H),1.47 (d, J=7.4 Hz, 3H), 1.29 (t, J=7.2Hz, 3H).

EXAMPLE 2(11)2-methyl-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid ethyl ester

[0269]

[0270] TLC: Rf 0.55(ethyl acetate:hexane=1:2); NMR(CDCl3): δ 7.87 (d,J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 4.15 (t,J=2.0 Hz, 2H), 3.77 (t, J=7.0 Hz, 2H), 3.42 (t, J=2.0 Hz, 2H), 2.78 (t,J=7.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 1.53 (s, 6H), 1.28 (t, J=7.0Hz, 3H).

EXAMPLE 2(12)1-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester

[0271]

[0272] TLC: Rf 0.51 (ethyl acetate:hexane=1:2); NMR(CDCl3): δ 7.87 (d,J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 4.19 (q, J=7.0 Hz, 2H), 4.15 (t,J=2.0 Hz, 2H), 3.77 (t, J=7.0 Hz, 2H), 3.35 (t, J=2.0 Hz, 2H), 2.78 (t,J=7.0 Hz, 2H), 2.62 (m, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.30-2.10 (m,3H), 1.90 (m,1H), 1.28 (t, J=7.0 Hz, 3H).

EXAMPLE 2(13) 2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)acetic acid ethyl ester

[0273]

[0274] TLC: Rf 0.26(hexane:ethyl acetate=2:1); NMR(CDCl3): δ 7.83 (d,J=9.0 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 4.19 (t, J=2.0 Hz, 2H), 4.18 (q,J=7.2 Hz, 2H), 3.77 (t, J=7.2 Hz, 2H), 3.45 (t, J=2.0 Hz, 2H), 3.38 (s,2H), 3.01 (s, 6H), 2.77 (t, J=7.2 Hz, 2H), 2.31 (s, 3H), 1.28 (t, J=7.2Hz, 3H).

EXAMPLE 2(14)2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2-butynytthio)aceticacid methyl ester

[0275]

[0276] TLC: Rf 0.47(hexane:ethyl acetate=1:1); NMR(CDCl3): δ 8.73 (m,1H), 7.99 (dd, J=9.0, 2.5 Hz, 1H), 6.52 (m, 1H), 4.20 (t, J=2.0 Hz, 2H),3.77 (t, J=7.0 Hz, 2H), 3.74 (s, 3H), 3.44 (t, J=2.0 Hz, 2H), 3.40 (s,2H), 3.15 (s, 6H), 2.76 (t, J=7.0 Hz, 2H), 2.32 (s, 3H).

EXAMPLE 2(15)2-methyl-2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid ethyl ester

[0277]

[0278] TLC: Rf 0.36(hexane:ethyl acetate=2:1); NMR(CDCl3): δ 7.83 (d,J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 4.16 (t,J=2.0 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H), 3.42 (t, J=2.0 Hz, 2H), 3.01 (s,6H), 2.76 (t, J=7.2 Hz, 2H), 2.31 (s, 3H), 1.54 (s, 6H), 1.28 (t, J=7.2Hz, 3H).

EXAMPLE 2(16)1-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester

[0279]

[0280] TLC: Rf 0.34(hexane:ethyl acetate=2:1); NMR(CDCl3): δ 7.83 (d,J=9.0 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 4.15 (t,J=2.0 Hz, 2H), 3.76 (t, J=7.0 Hz, 2H), 3.35 (t, J=2.0 Hz, 2H), 3.01 (s,6H), 2.76 (t, J=7.0 Hz, 2H), 2.71-2.53 (m, 2H), 2.31 (s, 3H), 2.28-2.12(m, 2H), 1.99-1.68 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).

EXAMPLE 2(17) 2-methyl-2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoic acidethyl ester

[0281]

[0282] TLC: Rf 0.22(hexane:ethyl acetate=2:1); NMR(CDCl3): δ 8.73 (dd,J=2.4, 0.6 Hz, 1H), 7.99 (dd, J=9.0, 2.4 Hz, 1H), 6.52 (dd, J=9.0, 0.6Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.08 (t, J=2.0 Hz, 2H), 4.04 (t, J=2.0Hz, 2H), 3.58 (t, J=7.2 Hz, 2H), 3.14 (s, 6H), 2.61 (t, J=7.2 Hz, 2.31(s, 3H), 1.57 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).

EXAMPLE 2(18)1-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester

[0283]

[0284] TLC: Rf 0.22(hexane:ethyl acetate=2:1); NMR(CDCl3): δ 8.73 (dd,J=2.4, 0.6 Hz, 1H), 7.99 (dd, J=9.0, 2.4 Hz, 1H), 6.52 (dd, J=9.0, 0.6Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.06 (t, J=2.0 Hz, 2H), 4.03 (t, J=2.0Hz, 2H), 3.14 (s, 6H), 2.75-2.54 (m, 4H), 2.31 (s, 3H), 2.27-2.08 (m,3H), 2.00-1.83 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).

EXAMPLE 3 2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)aceticacid methyl ester

[0285]

[0286] A compound prepared in Reference Example 7 (1.76 g),mercaptoacetic acid methyl ester (0.68 ml) and potassium carbonate (2.07g) were dissolved into acetonitrile (20 ml). Thereto, potassium iodide(83 mg) was added at room temperature. The mixture was refluxed for 2hours. The reaction mixture was cooled to room temperature and added toiced water. The mixture was extracted with ether. The extract was washedby 1N—NaOH solution, water and an aqueous saturated solution of sodiumchloride sucessively, dried over anhydrous magnesium sulfate andconcentrated to obtain the compound (1.72 g) of the present inventionhaving the following physical data.

[0287] TLC: Rf 0.20 (ethyl acetate:hexane=1:5); NMR (CDCl₃): δ 7.97 (m,2H), 7.50-7.35 (m, 3H), 3.73 (s, 3H), 3.68 (t, J=7.0 Hz, 2H), 3.44 (t,J=6.0 Hz, 2H), 3.21 (s, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.61 (t, J=7.0 Hz,2H), 2.34 (s, 3H), 1.75-1.35 (m, 6H).

EXAMPLE 4-EXAMPLE 4(1)

[0288] By the same procedures described in Reference Example 7→Example3, the following compounds of the present invention were obtained.

[0289] In the procedure of Reference Example 7, the following compoundswere used as starting materials.

EXAMPLE 4 1,4-dibromobutane and 2-(5-methyl-2-phenyloxazol-4-yl)ethanolEXAMPLE 4(1) 1,3-dibromopropane and2-(5-methyl-2-phenyloxazol-4-yl)ethanol EXAMPLE 42-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acidmethyl ester

[0290]

[0291] TLC: Rf 0.32 (ethyl acetate:hexane=1:3); NMR (CDCl₃): δ 7.98 (m,2H), 7.50-7.35 (m, 3H), 3.73 (s, 3H), 3.68 (t, J=7.0 Hz, 2H), 3.46 (m,2H), 3.20 (s, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.64 (m, 2H), 2.34 (s, 3H),1.70-1.60 (m, 4H).

EXAMPLE 4(1)2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)acetic acidmethyl ester

[0292]

[0293] TLC: Rf 0.15 (ethyl acetate:hexane=1:5); NMR (CDCl₃): δ 7.97 (m,2H), 7.50-7.35 (m, 3H), 3.72 (s, 3H), 3.69 (t, J=6.5 Hz, 2H), 3.53 (t,J=6.0 Hz, 2H), 3.21 (s, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.70 (t, J=6.5 Hz,2H), 2.34 (s, 3H), 1.85 (m, 2H).

EXAMPLE 5 2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio) acetic acid

[0294]

[0295] A compound prepared in Example 1 (270 mg) was dissolved intomixture solvent (10 ml, methanol:tetrahydrofuran=1:1). Thereto, 1N NaOHsolution (3.75 ml) was added at room temperature. The mixture wasstirred for 2 hours and then neutralized by addition of HCl. The mixturewas extracted with ethyl acetate. The extract was washed by water and anaqueous saturated solution of sodium chloride sucessively, dried overanhydrous magnesium sulfate and concentrated to obtain the compound (240mg) of the present invention having the following physical data.

[0296] TLC: Rf 0.33 (water: methanol:chloroform=1:10:100); NMR (CDCl₃):δ 7.95 (m, 2H), 7.50-7.40 (m, 3H), 5.82 (dt, J=15.0, 6.5 Hz, 1H), 5.67(dt, J=15.0, 5.0 Hz, 1H), 4.01 (d, J=5.0 Hz, 2H), 3.66 (t, J=8.0 Hz,2H), 3.31 (s, 2H), 3.28 (d, J=6.5 Hz, 2H), 2.83 (t, J=8.0 Hz, 2H), 2.35(s, 3H).

EXAMPLE 5(1)-EXAMPLE 5(17)

[0297] By the same procedure described in Example 5 using compoundsprepared in Example 2 to Example 2(5), Example 3, Example 4 to Example4(1), Example 2(6) to Example 2(9) and Example 2(11) to 2(14), thefollowing compounds of the present invention were obtained

[0298] In case of Example 5(10), Example 5(12) and Example 5(13),recrestallization from mixture solvent of ethyl acetate-hexane wasfollowed after the procedure described in Example 5.

EXAMPLE 5(1)2-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid

[0299]

[0300] TLC: Rf 0.32 (water:methanol:chloroform=1:10:100); NMR (CDCl₃): δ8.65 (br., 1H), 7.96 (m, 2H), 7.50-7.40 (m, 3H), 5.78 (m,1H), 5.59 (m,1H), 4.05 (d, J=6.0 Hz, 2H), 3.67 (t, J=7.0 Hz, 2H), 3.41 (d, J=8.0 Hz,2H), 3.30 (s, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.34 (s, 3H).

EXAMPLE 5(2)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acid

[0301]

[0302] TLC: Rf 0.28(water:methanol:chloroform=1:10:100); NMR (CDCl₃): δ7.97 (m, 2H), 7.50-7.40 (m, 3H), 4.23 (t, J=2.0 Hz, 2H), 3.81 (t, J=7.0Hz, 2H), 3.47 (t, J=2.0 Hz, 2H), 3.46 (s, 2H), 2.87 (t, J=7.0 Hz, 2H),2.35 (s, 3H).

EXAMPLE 5(3)2-((2E)-2-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid

[0303]

[0304] TLC: Rf 0.39 (chloroform:methanol=15:1); NMR (CDCl₃): δ 7.99-7.87(m, 2H), 7.48-7.38 (m, 3H), 5.52 (dt, J=7.0,1.5 Hz, 1H), 4.05 (d, J=7.0Hz, 2H), 3.61 (t, J=8.0 Hz, 2H), 3.30 (s, 2H), 3.22 (s, 2H), 2.79 (t,J=8.0 Hz, 2H), 2.34 (s, 3H), 1.82 (d, J=1.5 Hz, 3H).

EXAMPLE 5(4)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid

[0305]

[0306] TLC: Rf 0.44 (chloroform:methanol=3:1); NMR (CDCl₃): δ 7.98-7.86(m, 2H), 7.48-7.36 (m, 3H), 5.65 (t, J=8.0 Hz, 1H), 3.92 (s, 2H), 3.63(t, J=8.0 Hz, 2H), 3.36-3.24 (m, 4H), 2.84 (t, J=8.0 Hz, 2H), 2.35 (s,3H), 1.69 (s, 3H).

EXAMPLE 5(5) 2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid

[0307]

[0308] TLC: Rf 0.67 (chloroform:methanol=5:1); NMR (CDCl₃): δ 7.82 (d,J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 5.60-5.90 (m, 2H), 4.00 (d, J=5.4Hz, 2H), 3.65 (t, J=8.3 Hz, 2H), 3.31 (s, 2H), 3.27 (d, J=6.8 Hz, 2H),2.81 (t, J=8.3 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H).

EXAMPLE 5(6)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2butenylthio)aceticacid

[0309]

[0310] TLC: Rf 0.59 (chloroform:methanol=5:1); NMR (CDCl₃): δ 7.49 (dd,J=8.3, 1.7 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 6.02(s, 2H), 5.59-5.90 (m, 2H), 4.00 (d, J=4.8 Hz, 2H), 3.64 (t, J=8.0 Hz,2H), 3.31 (s, 2H), 3.27 (d, J=7.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.32(s, 3H).

EXAMPLE 5(7)2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)acetic acid

[0311]

[0312] TLC: Rf 0.33 (water:methanol:chloroform=1:10:100); NMR(CDCl_(3): δ) 7.97 (m, 2H), 7.50-7.35 (m, 3H), 3.65 (t, J=7.5 Hz, 2H),3.49 (t, J=6.0 Hz, 2H), 3.24 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.68 (t,J=7.0 Hz, 2H), 2.34 (s, 3H), 1.80-1.40 (m, 6H).

EXAMPLE 5(8)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acid

[0313]

[0314] TLC: Rf 0.33 (chloroform:methanol=10:1); NMR (CDCl₃): δ 8.00-7.95(m, 2H), 7.45-7.41 (m, 3H), 3.63 (t, J=7.5 Hz, 2H), 3.55 (m, 2H), 3.27(s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H), 2.34 (s, 3H),1.77-1.71 (m, 4H).

EXAMPLE 5(9)2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)acetic acid

[0315]

[0316] TLC: Rf 0.29 (water:methanol:chloroform=1:10:100) NMR (CDCl₃): δ7.97 (m, 2H), 7.50-7.35 (m, 3H), 3.68 (t, J=7.0 Hz, 2H), 3.61 (t, J=6.5Hz, 2H), 3.24 (s, 2H), 2.81 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H),2.34 (s, 3H), 1.86 (m, 2H).

EXAMPLE 5(10)2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0317]

[0318] TLC: Rf 0.43 (water:methanol:chloroform=1:10:100); NMR (CDCl₃) δ7.84 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.23 (t, J=2.0 Hz, 2H),3.81 (t, J=8.0 Hz, 2H), 3.47 (t, J=2.0 Hz, 2H), 3.46 (s, 2H), 2.86 (t,J=8.0 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H).

EXAMPLE 5(11)2-(4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0319]

[0320] TLC: Rf 0.39 (water:methanol:chloroform=1:10:100); NMR (CDCl₃): δ7.52 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (d, J=1.5 Hz, 1H), 6.86 (d, J=8.0 Hz,1H), 6.03 (s, 2H), 4.22 (t, J=2.0 Hz, 2H), 3.80 (t, J=8.0 Hz, 2H), 3.47(t, J=2.0 Hz, 2H), 3.46 (s, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.32 (s, 3H).

EXAMPLE 5(12)2-(4-(2-(5-methyl-2-(4-ethylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0321]

[0322] TLC: Rf 0.43 (water:methanol:chloroform=1:10:100); NMR (CDCl₃): δ7.87 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 4.23 (t, J=2.0 Hz, 2H),3.81 (t, J=8.0 Hz, 2H), 3.47 (t, J=2.0 Hz, 2H), 3.46 (s, 2H), 2.86 (t,J=8.0 Hz, 2H), 2.69 (q, J=7.5 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J=7.5 Hz,3H).

EXAMPLE 5(13)2-(4-(2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0323]

[0324] TLC: Rf 0.43 (water:methanol:chloroform=1:10:100); NMR (CDCl₃): δ7.87 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.23 (t, J=2.0 Hz, 2H),3.81 (t, J=8.0 Hz, 2H), 3.48 (t, J=2.0 Hz, 2H), 3.47 (s, 2H), 2.86 (t,J=8.0 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.34 (s, 3H), 1.66 (m, 2H), 0.94(t, J=7.5 Hz, 3H).

EXAMPLE 5(14)2-methyl-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid

[0325]

[0326] TLC: Rf 0.30(methanol:chloroform=1:50); NMR(CDCl3): δ 7.84 (d,J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.21 (t, J=2.0 Hz, 2H), 3.88 (t,J=7.0 Hz, 2H), 3.45 (t, J=2.0 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.39 (s,3H), 2.33 (s, 3H), 1.60 (s, 6H).

EXAMPLE 5(15)1-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid

[0327]

[0328] TLC: Rf 0.26(methanol:chloroform=1:50); NMR(CDCl3): δ 7.85 (d,J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 4.20 (t, J=2.0 Hz, 2H), 3.88 (t,J=8.5 Hz, 2H), 3.38 (t, J=2.0 Hz, 2H), 2.89 (t, J=8.5 Hz, 2H), 2.74 (m,2H), 2.39 (s, 3H), 2.36 (s, 3H ), 2.30-1.80 (m, 4H).

EXAMPLE 5(16)2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0329]

[0330] TLC: Rf 0.58 (chloroform:methanol=4:1); NMR(CDCl3): δ 7.82 (d,J=9.0 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 4.22 (t, J=2.0 Hz, 2H), 3.80 (t,J=8.4 Hz, 2H), 3.47 (t, J=2.0 Hz, 2H), 3.46 (s, 2H), 3.03 (s, 6H), 2.84(t, J=8.4 Hz, 2H), 2.31 (s, 3H).

EXAMPLE 5(17)2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid

[0331]

[0332] TLC: Rf 0.43(chloroform:methanol=10:1); NMR(CDCl3): δ 8.73 (d,J=2.5 Hz, 1H), 7.99 (dd, J=9.0, 2.5 Hz, 1H), 6.54 (d, J=9.0 Hz, 1H),4.22 (t, J=2.0 Hz, 2H), 3.80 (t, J=8.2 Hz, 2H), 3.47 (t, J=2.0 Hz, 2H),3.46 (s, 2H), 3.15 (s, 6H), 2.84 (t, J=8.2 Hz, 2H), 2.32 (s, 3H).

EXAMPLE 62-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt

[0333]

[0334] A compound prepared in Example 5 (208 mg) was dissolved intodioxane (5 ml). Thereto, 1N—NaOH (0.60 ml) was added at roomtemperature. The mixture was stirred for 1 hour. The reaction mixturewas freezed-dry to obtain the compound (192 mg) of the present inventionhaving the following physical data.

[0335] TLC: Rf 0.33 (water:methanol:chloroform=1:10:100); NMR (DMSO-d₆):δ 7.90 (m, 2H), 7.55-7.40 (m, 3H), 5.63 (dt, J=15.0, 6.0 Hz,1H), 5.51(dt, J=15.0, 4.5 Hz, 1H), 3.91 (d, J=4.5 Hz, 2H), 3.59 (t, J=7.0 Hz,2H), 3.09 (d, J=6.0 Hz, 2H), 2.83 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.32(s, 3H).

EXAMPLE 6(1)-EXAMPLE 6(8)

[0336] By the same procedure described in Example 6 using compoundsprepared in Example 5(1) to Example 5(2) and Example 5(4) to Example5(9), the following compounds of the present invention were obtained

EXAMPLE 6(1)2-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt

[0337]

[0338] TLC: Rf 0.33 (water:methanol:chloroform=1:10:100); NMR (DMSO-d₆):δ 7.90 (m, 2H), 7.55-7.40 (m, 3H), 5.65-5.40 (m, 2H), 4.05 (m, 2H), 3.61(t, J=7.0 Hz, 2H), 3.18 (m, 2H), 2.86 (s, 2H), 2.70 (t, J=7.0 Hz, 2H),2.34 (s, 3H).

EXAMPLE 6(2)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acidsodium salt

[0339]

[0340] TLC: Rf 0.43 (chloroform:methanol=9:1); NMR (DMSO-d₆): δ7.87-7.92 (m, 2H), 7.46-7.51 (m, 3H), 4.16 (t, J=2.0 Hz, 2H), 3.66 (t,J=6.8 Hz, 2H), 3.38 (t, J=2.0 Hz, 2H), 3.05 (s, 2H), 2.71 (t, J=6.8 Hz,2H), 2.32 (s, 3H).

EXAMPLE 6(3)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt

[0341]

[0342] TLC: Rf 0.44 (chloroform:methanol=15:1); NMR (CDCl₃): δ 7.98-7.84(m, 2H), 7.42-7.29 (m, 3H), 5.44 (t, J=7.5 Hz, 1H), 3.79 (s, 2H), 3.57(t, J=7.0 Hz, 2H), 3.18 (s, 2H), 3.13 (d, J=7.5 Hz, 2H), 2.71 (t, J=7.0Hz, 2H), 2.26 (s, 3H), 1.57 (s, 3H).

EXAMPLE 6(4)2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt

[0343]

[0344] TLC: Rf 0.62 (chloroform:methanol=5:1); NMR (DMSO-d₆): δ 7.78 (d,J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.46-5.70 (m, 2H), 3.91 (d, J=4.2Hz, 2H), 3.58 (t, J=7.0 Hz, 2H), 3.10 (d, J=5.4 Hz, 2.86 (s, 2H), 2.68(t, J=7.0 Hz, 2H), 2.34 (s, 3H), 2.31 (s, 3H).

EXAMPLE 6(5)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2butenylthio)aceticacid sodium salt

[0345]

[0346] TLC: Rf 0.56 (chloroform:methanol=5:1); NMR (DMSO-d₆): δ 7.42(dd, J=8.2, 1.7 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H),6.09 (s, 2H), 5.46-5.70 (m, 2H), 3.91 (d, J=2.8 Hz, 2H), 3.57 (t, J=7.0Hz, 2H), 3.10 (d, J=5.6 Hz, 2H), 2.86 (s, 2H), 2.66 (t, J=7.0 Hz, 2H),2.29 (s, 3H).

EXAMPLE 6(6)2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)acetic acidsodium salt

[0347]

[0348] TLC: Rf 0.33 (water:methanol:chloroform=1:10:100); NMR (DMSO-d₆):δ 7.90 (m, 2H), 7.55-7.40 (m, 3H), 3.59 (t, J=7.0 Hz, 2H), 3.38 (t,J=6.0 Hz, 2H), 2.89 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.5 Hz,2.33 (s, 3H), 1.60-1.20 (m, 6H).

EXAMPLE 6(7)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acidsodium salt

[0349]

[0350] TLC: Rf 0.33 (water:methanol:chloroform=1:10:100); NMR (DMSO-d₆):δ 7.90 (m, 2H), 7.55-7.40 (m, 3H), 3.59 (t, J=7.0 Hz, 2H), 3.39 (t,J=6.0 Hz, 2H), 2.88 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.46 (t, J=6.5 Hz,2H), 2.33 (s, 3H), 1.65-1.40 (m, 4H).

EXAMPLE 6(8)2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)acetic acidsodium salt

[0351]

[0352] TLC: Rf 0.29 (water:methanol:chloroform=1:10:100); NMR (DMSO-d₆):δ 7.90 (m, 2H), 7.55-7.40 (m, 3H), 3.59 (t, J=7.0 Hz, 2H), 3.45 (t,J=6.5 Hz, 2H), 2.91 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.50 (t, J=7.0 Hz,2H), 2.33 (s, 3H), 1.70 (m, 2H).

EXAMPLE 7(2RS)-2-(4-(2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid sodium salt

[0353]

[0354] By the same procedures described in Example 5→Example 6 using acompound prepared in Example 2(10), the compound of the presentinvention having the following physical data was obtained.

[0355] TLC: Rf 0.55 (ethyl acetate); NMR (CD₃OD): δ 7.83 (d, J=8.4 Hz,2H), 7.28 (d, J=8.4 Hz, 2H), 4.17 (t, J=2.0 Hz, 2H), 3.75 (t, J=6.6 Hz,2H), 3.51 (q, J=7.0 Hz, 1H), 3.41-3.35 (t, J=2.0 Hz, 2H), 2.76 (t, J=6.6Hz, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 1.41 (d, J=7.0 Hz, 3H).

EXAMPLE 82-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylsulfino)aceticacid

[0356]

[0357] To a solution of a compound prepared in Example 5(10) (1.002 g)in THF (200 ml), a solution of OXONE (trade name) (1.029 g) in water(100 ml) was added at 0° C. The mixture was stirred at 0° C. for 20minutes. The reaction mixture was poured into iced water and extractedwith ethyl acetate. The extract was washed by water and an aqueoussaturated solution of sodium chloride, sucessively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with silicagel column chromatography(chloroform:methanol=50:1→20:1→chloroform:methanol:water=4:1:0.1) toobtain the title compound (0.5994 g) having the following physical data.

[0358] TLC: Rf 0.20(chloroform:methanol:acetic acid=9:1:0.3);NMR(CDCl3): δ 7.82 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 4.18 (m,2H), 3.64-3.98 (m, 6H), 2.76 (t, J=6.9 Hz, 2H), 2.36 (s, 3H), 2.30 (s,3H).

EXAMPLE 9 2-(4-(2-(5-methyl -2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylsulfonyl)acetic acid

[0359]

[0360] To a solution of a compound prepared in Example 5(10) (1.000 g)in THF (20 ml), a solution of OXONE (trade name) (3.421 g) in water (10ml) was added at 0° C. The mixture was stirred at room temperature for 4hours. The reaction mixture was poured into iced water and extractedwith ethyl acetate. The extract was washed by water and an aqueoussaturated solution of sodium chloride, sucessively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with silicagel column chromatography (chloroform:methanol=20:1) to obtain the titlecompound (0.678 g) having the following physical data.

[0361] TLC: Rf 0.58(chloroform:methanol:acetic acid=50:20:1);NMR(CDCl3): δ 7.86 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 4.22-4.26(m, 6H), 3.76 (t, J=8.1Hz, 2H), 2.85 (t, J=8.1Hz, 2H), 2.41 (s, 3H),2.35 (s, 3H).

REFERENCE EXAMPLE 8 5-hexynoic acid (3-methyloxetan-3-yl)methyl ester

[0362]

[0363] To a solution of 5-hexynoic acid (10.0 g) and 3-methyl-3-oxetanemethanol (10.0 g) in methylene chloride (50 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.5 g),and 4-dimethylaminopyridine (1.09 g) were added under cooling with ice.The mixture was stirred at room temperature for 45 minutes. The reactionmixture was poured into iced water and extracted with ethyl acetate. Theorgnic layer was washed by water and an aqueous saturated solution ofsodium chloride, sucessively, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified with silica gel columnchromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound(16.7 g) having the following physical data.

[0364] TLC: Rf 0.38(n-hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 4.52 (d,J=6.0 Hz, 2H), 4.42 (d, J=6.0 Hz, 2H), 4.18 (s, 2H), 2.52 (t, J=7.0 Hz,2H), 2.29 (dt, J=2.6, 7.0 Hz, 2H), 1.98 (dt, J=2.6 Hz, 1H), 1.87 (tt,J=7.0, 7.0 Hz, 2H), 1.34 (s, 3H).

REFERENCE EXAMPLE 91-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-4-hexyne

[0365]

[0366] To a solution of a compound prepared in Reference Example 8 (16.7g) in methylene chloride (200 ml), trifluoro borodiethylether complex(2.6 ml) was added at −20° C. The mixture was stirred at 0° C.overnight. To the reaction mixture, triethylamine (11.85 ml) was added.The mixture was filtered by Celite (trade mark). The filtrate wasconcentrated. The residue was purified with silica gel columnchromatography (1% triethylamine-methylene chloride) to obtain the titlecompound (14.7 g) having the following physical data.

[0367] TLC: Rf 0.58(n-hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 3.89 (s,6H), 2.22 (dt, J=2.7, 6.6 Hz, 2H), 1.93 (dt, J=2.7 Hz, 1H), 1.60-1.84(m, 4H), 0.80 (s, 3H).

REFERENCE EXAMPLE 106-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-2-hexyne-1-ol

[0368]

[0369] To a solution of a compound prepared in Reference Example 9 (7.58g) in THF (70 ml), a solution of 1.6 M n-butyllithium hexane (26.6 ml)was added at −78° C. The mixture was stirred for at −78° C. for 10minutes. Thereto, p-formaldehyde (1.93 g) was added. The mixture wasstirred at room temperature for 5 hours. The reaction mixture was pouredinto iced water and extracted with ethyl acetate. The orgnic layer waswashed by an aqueous saturated solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedwith silica gel column chromatography (n-hexane:ethyl acetate=2:1,containing 1% triethylamine) to obtain the title compound (6.21 g)having the following physical data.

[0370] TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 4.22 (t,J=2.2 Hz, 2H), 3.89 (s, 6H), 2.25 (dt, J=7.0, 2.2 Hz, 2H), 1.55-1.83 (m,4H), 0.80 (s, 3H).

REFERENCE EXAMPLE 111-iodo-6-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-2-hexyne

[0371]

[0372] To a solution of a compound prepared in Reference Example 10(6.21 g) in benzene (130 ml), triphenyphosphine (9.36 ml) and imidazole(2.17 g) were added. To the mixture, iodide (8.36 g) was added undercooling with ice. The mixture was stirred at room temperature for 4.5hours. The reaction mixture was filtered by Celite (trade mark) andfiltrate was concentrated. The residue was purified with silica gelcolumn chromatography (n-hexane:ethyl acetate=25:1→5:1, containing 1%triethylamine) to obtain the title compound (1.90 g) having thefollowing physical data.

[0373] TLC: Rf 0.62 (n-hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 3.89 (s,6H), 3.69 (t, J 2.4 Hz, 2H), 2.23 (tt, J=6.8, 2.4 Hz, 2H), 1.57-1.80 (m,4H), 0.80 (s, 3H).

REFERENCE EXAMPLE 121-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-6-(4-methyl-2,6,7trioxabicyclo]2.2.2[octan-1-yl)-2-hexyne

[0374]

[0375] 2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethanol (0.65 g)was dissolved into mixture solvent of THF/DMF (1:1) (14 ml). Thereto,sodium hydroxide (0.116 g) was added under cooling with ice. The mixturewas stirred at room temperature for 2 hours. To the reaction mixture, asolution of a compound prepared in Reference Example 11 (0.93 g) in THF(7 ml) was added. The mixture was stirred at room temperature for 6hours and then at 50° C. overnight. The reaction mixture was poured intoiced water (containing 3 ml of triethylamine) and extracted with ethylacetate. The orgnic layer was washed by water and an aqueous saturatedsolution of sodium chloride, sucessively, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified with silica gelcolumn chromatography (n-hexane:ethyl acetate=2:1) to obtain the titlecompound (0.393 g) having the following physical data.

[0376] TLC: Rf 0.39(n-hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.52 (dd,J=8.4, 1.6 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.01(s, 2H), 4.12 (t, J=2.2 Hz, 2H), 3.88 (s, 6H), 3.74 (t, J=7.0 Hz, 2H),2.76 (t, J=7.0 Hz, 2H), 2.32 (s, 3H), 2.24 (tt, J=6.8, 2.2 Hz, 2H),1.60-1.83 (m, 4H), 0.79 (s, 3H).

EXAMPLE 107-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-5-heptynoicacid

[0377]

[0378] A compound prepared in Reference Example 12 (0.393 g) wasdissolved into 1,4-dioxane (5 ml). Thereto, 1 M HCl (2.2 ml) was addedunder cooling with ice. The mixture was stirred at room temperature for30 minutes and then cooled with ice again. Thereto, a solution of 2 Msodium hydroxide (3.2 ml) was added. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into iced water.The back-extraction of the mixture with diethyl ether was carried out.Water layer was acidified by hydrochloric acid and extracted with ethylacetate. The orgnic layer was washed by water and an aqueous saturatedsolution of sodium chloride, sucessively, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified with silica gelcolumn chromatography (chloroform:methanol=100:1) to obtain the titlecompound (0.276 g) having the following physical data.

[0379] TLC: Rf 0.39(chloroform:methanol=15:1); NMR(CDCl₃): δ 7.51 (dd,J=8.0, 1.6 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.02(s, 2H), 4.16 (t, J=2.1Hz, 2H), 3.78 (t, J=7.6 Hz, 2H), 2.81 (t, J=7.6Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 2.37 (m, 2H), 2.32 (s, 3H), 1.90 (tt,J=6.5, 6.2 Hz, 2H).

EXAMPLE 117-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-5-heptynoic acid

[0380]

[0381] By the same procedures described in Reference Example 12→Example10 using 2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethanol, the titlecompound having the following physical data was obtained.

[0382] TLC: Rf 0.38(chloroform:methanol=15:1); NMR(CDCl3): δ 7.85 (d,J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 4.16 (t, J=2.1 Hz, 2H), 3.79 (t,J=7.8 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 2.39 (s,3H), 2.37 (m, 2 H), 2.34 (s, 3H), 1.89 (tt, J=6.5, 6.5 Hz, 2H).

FORMULATION EXAMPLE FORMULATION EXAMPLE 1

[0383] The following compounds were admixed in conventional method andpunched out to obtain 100 tablets each containing 100 mg of activeingredient. 2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2- 10.0g  butenylthio)acetic acid Cellulose calcium glycolate (disintegratingagent) 0.2 g Magnesium stearate (lubricating agent) 0.1 g Microcrystalline cellulose 9.7 g

FORMULATION EXAMPLE 2

[0384] The following components were admixed in a conventional method,and the solution was sterilized in a conventional method, placed 5 mlportions into ampoules and freeze-dried in a conventional method toobtain 100 ampoules each containing 20 mg of active ingredient.2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2- 2.0 gbutenylthio)acetic acid Mannit 5.0 g Distilled water 500 ml

[0385]

1 3 1 85 DNA Artificial sequence Enhancer sequence including 4 timesrepeated Gal4 protein response sequences 1 tcgacggagt actgtcctccgcgacggagt actgtcctcc gcgacggagt actgtcctcc 60 gcgacggagt actgtcctccgagct 85 2 9 PRT Unknown Nuclear localozation signal derived from SV-40T-antigen 2 Ala Pro Lys Lys Lys Arg Lys Val Gly 1 5 3 9 PRT Influenzavirus hemagglutinin epitope 3 Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1 5

1. A compound of the formula (I)

(wherein, A¹ is C1-4 alkylene, A² is C2-8 alkylene, C3-8 alkenylene orC3-8 alkynylene, E¹ is —O— or —S—, E² is —CH₂—, —O— or —S(O)_(m)—. m is0, 1 or 2, each R¹ in (R¹)n independently, is hydrogen, C1-8 alkyl,halogen, C1-4 alkoxy, C1-4 alkylthio, nitro, NR⁷R⁸ (in which R⁷ and R⁸each independently, is C1-4 alkyl), cyano, trifluoromethyl,trifluoromethyloxy, carbocyclic ring or heterocyclic ring (in whichcarbocyclic ring and heterocyclic ring may be substituted with the groupselected from C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl), R²is hydrogen, C1-8 alkyl, halogen, C1-4 alkoxy, C1-4 alkylthio, nitro,NR⁷R⁸ (in which R⁷ and R⁸ each independently, is C1-4 alkyl), cyano,trifluoromethyl or trifluoromethyloxy, R³ and R⁴ each independently, ishydrogen or C1-4 alkyl or R³ and R⁴ taken together with carbon atom towhich is attached represents C3-7 cycloalkylene, R⁵ is —COOR⁹ (in whichR⁹ is hydrogen or C1-4 alkyl) or heterocyclic ring which is equivalentto carboxylic acid,

 each independently, is carbocyclic ring or heterocyclic ring and  n is1-3)  or non-toxic salt thereof, or hydrate thereof.
 2. A compoundaccording to claim 1, wherein Cyc1 is

or non-toxic salt thereof, or hydrate thereof.
 3. A compound accordingto claim 1, wherein A² is C3-8 alkynylene or non-toxic salt thereof, orhydrate thereof.
 4. A compound according to claim 1, wherein R⁵ is—COOR⁹ (in which R⁹ is hydrogen or C1-4 alkyl) or non-toxic saltthereof, or hydrate thereof.
 5. A compound according to claim 1, whereinR⁵ is —COOR⁹ (in which R⁹ is hydrogen or C1-4 alkyl), A² is C3-8alkynylene, Cyc1 is

or non-toxic salt thereof, or hydrate thereof.
 6. A compound accordingto claim 1, which is (1)2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester, (2)2-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester, (3)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acidmethyl ester, (4)2-((2E)-2-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2butenylthio)aceticacid methyl ester, (5)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2butenylthio)aceticacid methyl ester, (6)2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester, (7)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid methyl ester, (8)2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid methyl ester, (9)2-(4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid methyl ester, (10)2-(4-(2-(5-methyl-2-(4-ethylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid methyl ester, (11)2-(4-(2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid methyl ester, (12)(2RS)-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid methyl ester, (13)2-methyl-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid ethyl ester, (14)1-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester, (15)2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid ethyl ester, (16)2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2butynylthio)aceticacid methyl ester, (17)2-methyl-2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid ester, (18)1-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester, (19)2-methyl-2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4yl)ethoxy)-2-butynylthio)propanoicacid ethyl ester, (20)1-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid ethyl ester, (21)2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)acetic acidmethyl ester, (22)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acidmethyl ester, (23) 2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)acetic acid methyl ester, (24)2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid, (25)2-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid, (26)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acid,(27)2-((2E)-2-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2butenylthio)aceticacid, (28)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2butenylthio)aceticacid, (29)2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2butenylthio)aceticacid, (30)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2butenylthio)aceticacid, (31)2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)acetic acid,(32) 2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acid,(33) 2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)aceticacid, (34)2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid, (35)2-(4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid, (36)2-(4-(2-(5-methyl-2-(4-ethylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid, (37) 2-(4-(2-(5-methyl-2-(4-propylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)acetic acid, (38)2-methyl-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2butynylthio)aceticacid, (39)1-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)cyclobutanecarboxylic acid, (40)2-(4-(2-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-yl)ethoxy)-2-butynylthio)aceticacid, (41)2-(4-(2-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-yl)ethoxy)-2butynylthio)aceticacid, (42)2-((2E)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt, (43)2-((2Z)-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt, (44)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butynylthio)acetic acidsodium salt, (45)2-((2E)-3-methyl-4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt, (46)2-((2E)-4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt, (47)2-((2E)-4-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-2-butenylthio)aceticacid sodium salt, (48)2-(5-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)pentylthio)acetic acidsodium salt, (49)2-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)butylthio)acetic acidsodium salt, (50)2-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)propylthio)acetic acidsodium salt, (51)(2RS)-2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylthio)propanoicacid sodium salt, (52)2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylsulfino)aceticacid, (53)2-(4-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-2-butynylsulfonyl)aceticacid, (54)7-(2-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-yl)ethoxy)-5-heptynoicacid or (55)7-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-5-heptynoic acid,or non-toxic salt thereof, or hydrate thereof.
 7. A peroxisomeproliferator activated receptor regulator comprising a compound of theformula (I) depicted in claim 1, a non-toxic salt thereof or a hydratethereof as an active ingredient.
 8. A peroxisome proliferator activatedreceptor regulator according to claim 7, whose activity is PPARα agonistand/or PPARγ agonist, comprising a compound of the formula (I) depictedin claim 1, a non-toxic salt thereof or a hydrate thereof as an activeingredient.
 9. A hypoglycemic agent, hypolipidemic agent, preventiveand/or a remedy for diseases associated with metabolic disorders(diabetes, obesity, syndrome X, hypercholesterolemia,hyperlipoproteinemia etc.), hyperlipidemia, atherosclerosis,hypertension, circulatory diseases, overeating and coronary heartdiseases, an HDL cholesterol-elevating agent, an LDL cholesterol and/orVLDL cholesterol-lowering agent, an agent for relief from risk factor ofdiabetes or syndrome X comprising a compound of the formula (I) depictedin claim 1, a non-toxic acid thereof or a hydrate thereof as an activeingredient.